Stereocontrolled total synthesis of (+)-paraherquamide B

J. Am. Chem. Soc. 1996, 118, 557-579

557

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

Timothy D. Cushing,^‡Juan F. Sanz-Cervera,^†and Robert M. Williams*

Contribution from the Department of Chemistry, Colorado State UniVersity,

Fort Collins, Colorado 80523

ReceiVed August 7, 1995^X

Abstract: The convergent stereocontrolled, asymmetric total synthesis of (+)-paraherquamide B is described. Key

features of this synthesis include (1) an improved procedure to effect reduction of unprotected oxindoles to indoles;

(2) a complex application of the Somei/Kametani coupling reaction; (3) a high-yielding and entirely stereocontrolled

intramolecular S_N2′ cyclization reaction that constructs the core bicyclo[2.2.2] ring system; (4) a mild Pd(II)-mediated

cyclization reaction that constructs a complex tetrahydrocarbazole; and (5) the chemoselective reduction of a highly

hindered tertiary lactam in the presence of an unhindered secondary lactam, utilizing precoordination of the more

reactive secondary lactam to triethylaluminum.

Introduction

recently drug resistance to the avermectins has been observed

in various parasites.⁹The paraherquamides represent an entirely

new structural class of antiparasitic agents, which promise to

play a significant role in the near future. The relatively low

culture yields of paraherquamide obtained for biological study

have slowed the development and potential commercialization

of these agents (Figure 1).

As part of our ongoing efforts to elucidate the biosynthesis

of the core bicyclo[2.2.2] ring system of the related alkaloids

the brevianamides,¹⁰we have applied methodology originally

developed for the stereocontrolled total synthesis of (-)-

brevianamide B¹¹to complete the first stereocontrolled total

synthesis of (+)-paraherquamide B (12);¹²the results of this

study are described in full herein.

The paraherquamides are complex, heptacyclic, toxic mold

metabolites with potent anthelmintic activity isolated from

various Penicillium sp. The parent and most potent derivative,

paraherquamide A (1), was first isolated from Penicillium

parherquei in 1980 by Yamazaki.¹The simplest member,

paraherquamide B (2), plus five other structurally related

paraherquamides C-G (3-9) were isolated from Penicillium

charlesii (fellutanum) (ATCC 20841) in 1990 at Merck & Co.^2,3

and concomitantly at SmithKline Beecham.⁴More recently

three additional related compounds were discovered by the same

group at SmithKline.⁵Interest in the paraherquamides has come

from the finding that this class of alkaloids displays potent

anthelmintic and antinematodal properties.^6,7

The paraherquamides are structurally very similar to brevi-

anamides A and B (17 and 16)¹³and marcfortines A-C (13-

15)¹⁴with respect to the common core bicyclo[2.2.2] ring system

that is derived from the cycloaddition of an isoprene unit across

the amino acid R-carbons. This close structural similarity might

imply a related biogenesis, and the structural features of these

substances shall be described briefly from this standpoint. The

paraherquamides and brevianamides A and B (17 and 16) appear

to be derived from the condensation of tryptophan and proline,

while the marcfortines are formed from the condensation of

tryptophan and pipecolic acid. The origin of the methyl group

in the pyrrolidine ring of paraherquamides A and C-E and

VM55595-7 could in principle come from the methylation of

proline, but it seems more likely that this amino acid residue is

derived from isoleucine. The very low fermentation yield of

paraherquamide B may be a manifestation of poor incorporation

of cyclo-L-trp-L-pro into the subsequent biosynthetic machinery

There are essentially three classes of broad-spectrum anthel-

mintics currently in use: the benzimidazoles, the levamisoles/

morantels, and the avermectins/milbemycins. Unfortunately, the

first two groups have lost much of their utility due to the recent

appearance of drug resistance built up by the helminths.^7a,8More

Dedicated to Professor Ei-ichi Negishi on the occasion of his 60th

birthday.

^†On leave from the Department of Organic Chemistry of the University

of Valencia, Spain.

^‡Present address: Tularik Inc., 270 East Grand Ave., South San

Francisco, CA 94080.

^XAbstract published in AdVance ACS Abstracts, December 1, 1995.

(1) (a) Yamazaki, M.; Fujimoto, H.; Okuyama, E.; Ohta, Y. Proc. Jpn.

Assoc. Mycotoxicol. 1980, 10, 27. (b) Yamazaki, M.; Okuyama, E.;

Kobayashi, M.; Inoue, H. Tetrahedron Lett. 1981, 22, 135.

(2) (a) Blizzard, T. A.; Marino, G.; Mrozik, H.; Fisher, M. H.; Hoogsteen,

K.; Springer, J. P. J. Org. Chem. 1989, 54, 2657. (b) Blizzard, T. A.; Mrozik,

H.; Fisher, M. H.; Schaeffer, J. M. J. Org. Chem. 1990, 55, 2256. (c)

Blizzard, T. A.; Margiatto, G.; Mrozik, H.; Schaeffer, J. M.; Fisher, M. H.

Tetrahedron Lett. 1991, 32, 2437. (d) Blizzard, T. A.; Margiatto, G.; Mrozik,

H.; Schaeffer, J. M.; Fisher, M. H. Tetrahedron Lett. 1991, 32, 2441. (e)

Blizzard, T. A.; Rosegay, A.; Mrozik, H.; Fisher, M. H. J. Labelled Compd.

Radiopharm. 1990, 28, 461.

(8) Coles, G. C. Pestic. Sci. 1977, 8, 536.

(9) (a) Van Wyk, J. A.; Malan, F. S. Vet. Rec. 1988, 123, 226. (b)

Echevarria, F. A. M.; Trindade, N. P. Vet. Rec. 1989, 124, 147.

(10) (a) Sanz-Cervera, J. F.; Glinka, T.; Williams, R. M. J. Am. Chem.

Soc. 1993, 115, 347. (b) Sanz-Cervera, J. F.; Glinka, T.; Williams, R. M.

Tetrahedron 1993, 49, 8471.

(3) (a) Ondeyka, J. D.; Goegelman, R. T.; Schaeffer, J. M.; Kelemen, L.

J. Antibiot. 1990, 43, 1375. (b) Liesch, J. M.; Wichman, C. F. J. Antibiot.

1990, 43, 1380.

(4) Blanchflower, S. E.; Banks, R. M.; Everett, J. R.; Manger, B. R.;

Reading, C. J. Antibiot. 1991, 44, 492.

(5) Blanchflower, S. E.; Banks, R. M.; Everett, J. R.; Reading, C. J.

Antibiot. 1993, 46, 1355.

(11) (a) Williams, R. M.; Glinka, T.; Kwast, E. J. Am. Chem. Soc. 1988,

110, 5927. (b) Williams, R. M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille,

J. K. J. Am. Chem. Soc. 1990, 112, 808. (c) Williams, R. M.; Glinka, T.;

Kwast, E. Tetrahedron Lett. 1989, 30, 5575.

(6) Ostlind, D. A.; Mickle, W. G.; Ewanciw, D. V.; Andriuli, F. J.;

Campbell, W. C.; Hernandez, S.; Mochaeles, S.; Munguira, E. Res. Vet.

Sci. 1990, 48, 260.

(7) (a) Shoop, W. L.; Egerton, J. R.; Eary, C. H.; Suhayda, D. J. Parasitol.

1990, 76 (2) 186. (b) Shoop, W. L.; Michael, B. F.; Haines, H. W.; Eary,

C. H. Vet. Parasitol. 1992, 43, 259. (c) Schaeffer, J. M.; Blizzard, T. A.;

Ondeyka, J.; Goegelman, R.; Sinclair, P. J.; Mrozik, H. Biochem. Pharmacol.

1992, 43, 679. (d) Shoop, W. L.; Haines, H. W.; Eary, C. H.; Michael, B.

F. Am. J. Vet. Res. 1992, 53, 2032.

(12) A preliminary account of this work has appeared: Cushing, T. D.;

Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115, 9323.

(13) (a) Birch, A. J.; Wright, J. J. J. Chem. Soc., Chem. Commun. 1969,

644. (b) Birch, A. J.; Wright, J. J.; Tetrahedron 1970, 26, 2339. (c) Birch,

A. J.; Russell, R. A. Tetrahedron 1972, 28, 2999. (d) Baldas J.; Birch, A.

J.; Russell, R. A. J. Chem. Soc., Perkin Trans. 1 1974, 50.

(14) (a) Polonsky, J.; Merrien, M. A.; Prange, T; Pascard, C. J. Chem

Soc., Chem Commun. 1980, 601. (b) Prange, T.; Billion, M.-A.; Vuilhorgne,

M.; Pascard, C.; Polonsky, J. Tetrahedron Lett. 1981, 22, 1977.

558 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

Figure 1.

or may be the result of inefficient demethylation of the

isoleucine-derived amino acid precursor.

first task would involve the construction of a suitably R-alkylated

proline derivative.¹¹The second important coupling would be

the Somei/Kametani-type alkylation¹⁸of a suitably protected

gramine derivative (20) and the requisite piperazine-

dione (19). The third and perhaps most crucial C-C bond-

forming reaction, providing the core bicyclo[2.2.2] ring system,

was a stereofacially controlled intramolecular S_N2′ cyclization

reaction that sets the stereochemistry at C-20 (paraherquamide

numbering) and concomitantly installs the isopropenyl group

that will be utilized in the fourth C-C bond-forming reaction.

This isopropenyl group, in turn, would be conscripted for an

olefin-cation cyclization to provide the heptacyclic tetrahy-

drocarbazole. Standard procedures to effect this transformation

involve strong protic acids,^11,19and there was reason for concern

about the reactivity of the more highly oxygenated indole (22)

as a practical synthetic precursor to 23. The penultimate step,

a regio- and stereofacially controlled oxidative spirocyclization

reaction, must be accomplished to construct the desired spiro-

oxindole. A number of these transformations were explored

during the course of the investigations on the synthesis of (-)-

brevianamide B,¹¹including a simple oxindole model study,^11c

which set a firm foundation for addressing some of the

The oxidation state of the amino acid-derived dioxopiperazine

moiety remains unchanged in the case of the brevianamides,

but for the paraherquamides and the marcfortines the tertiary

amide residue is enzymatically reduced to a monooxopiperazine,

a process that is known.¹⁵The tryptophan-derived indolyl side

chain of the paraherquamides and marcfortines is oxidized to

spiro-oxindoles while the indolyl side chain of the brevianamides

oxidize to spiro-indoxyls. The paraherquamides, marcfortines,

and brevianamides all incorporate one isoprene unit that forms

the bridging bicyclo[2.2.2] ring structure. The paraherquamides

and marcfortines differ from the brevianamides in that a second

isoprene unit coupled with an oxidized form of tryptophan gives

the dioxepin (or pyran) moiety. This is one of the most

interesting and unique features of these compounds. The gem-

dimethyl dioxepin ring found in paraherquamides A-E (1-5)

and marcfortines A and B (13 and 14) is a unique ring system

among natural products. A similar structural feature was

discovered in the antifungal natural product strobilurin G (18),¹⁶

but this dioxepin moiety lacks the double bond found in the

other metabolites (Figure 1).

As outlined in Scheme 1, a convergent synthesis of the

enantiomer of paraherquamide B (12)¹⁷was envisioned to

contain four key carbon-carbon bond-forming reactions. The

(18) (a) Somei, M.; Karasawa, Y.; Kaneko, C. Heterocycles 1981, 16,

941. (b) Kametani, T.; Kanaya, N.; Ihara, M. J. Am. Chem. Soc. 1980, 102,

3974.

(15) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. V.; Steyn, P. S. J.

Chem. Soc., Perkin Trans. 1 1979, 1751.

(16) Fredenhagen, A.; Hug, P.; Peter, H. H. J. Antibiot. 1990, 48, 661.

(17) The enantiomer of the natural product was selected as the target

due to the large relative cost difference between (S)- and (R)-proline.

(19) (a) Stoermer, D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 564.

(b) Guller, R.; Dobler, M.; Borschberg, H.-J. HelV. Chim. Acta 1991, 74,

1636. (c) Darbre, T.; Nussbaumer, C.; Borschberg, H.-J. HelV. Chim. Acta

1984, 67, 1040. (d) Delpech, B.; Khuong-Huu, Q. J. Org. Chem. 1978, 43,

4898.

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 559

Scheme 1

Scheme 2

stereochemical and regiochemical issues that would be faced

in attacking the paraherquamide ring system.

employed a phenylselenoetherification.²²Following a procedure

of Clive,²³24 cyclized to 25 with either PhSeCl or N-

phenylselenophthalimide (N-PSP),²⁴although in very low yield.

The main byproducts came from the electrophilic addition across

the double bond, electrophilic aromatic substitution of the phenyl

ring by the phenyl selenide, and phenolic attack at the methylene

producing the six-membered-ring product. The selenide 25 was

treated with H₂O₂and the resulting selenoxide thermally

eliminated providing the unique dioxepin 26 in 49% yield.

Results and Discussion

Construction of the Dioxepinooxindole Ring System. The

prenylated catechol ring system of the paraherquamides is an

unusual oxidative cyclization product that previously has not

been observed to occur in metabolites of mixed biogenetic

origin. Although the parent 2H-1,5-benzodioxepin has been

synthesized previously,²⁰to the best of our knowledge there

has been no reported synthesis of the corresponding isoprenyl

dioxepin ring system of paraherquamide. The synthesis of this

ring system was explored in a simple model study employing

prenylated catechol 24 (Scheme 2).²¹It was speculated that

the requisite 7-endo-tet cyclization reaction would be facilitated

by a stabilized tertiary carbocation provided by the prenyl

substituent.

Due to the low yield of the phenylselenoetherification, an

alternative procedure involving epoxidation followed by a Lewis

acid-mediated ring closure was investigated.²⁵The prenylated

catechol 24 was epoxidized with buffered m-CPBA to provide

epoxide 27, which was treated with stannic chloride to give the

dioxepin 28. A major side product in this reaction was a ketone,

(22) (a) Nicolaou, K. C. Tetrahedron 1981, 37, 4097. (b) Nicolaou, K.

C.; Magolda, R. L.; Sipio, W. J.; Barnette, W. E.; Lysenko, Z.; Joullie, M.

M. J. Am. Chem. Soc. 1980, 102, 3784. (c) Clive, D. L. J. Tetrahedron

1978, 34, 1049-1132.

(23) (a) Clive, D. J. L.; Chiiattu, G.; Curtis, N. J.; Kiel, W. A.; Wong,

C. K. J. Chem. Soc., Chem. Commun. 1977, 725. See also: (b) Liotta, D.;

Zima, G. Tetrahedron Lett. 1978, 50, 4977. (c) Tiecco, M.; Testaferri, L.;

Tingoli, M.; Bartoli, D.; Balducci, R. J. Org. Chem. 1990, 55, 429.

(24) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J.

Am. Chem. Soc. 1979, 101, 3704.

The first attempt at effecting this cyclization reaction

(20) Guillaumet, G.; Coudert, G.; Loubinnoux, B. Angew. Chem., Int.

Ed. Engl. 1983, 22, 64.

(25) (a) Cookson, R. C.; Liverton, N. J. J. Chem. Soc., Perkin Trans. 1

1985, 1589. (b) Kocienski, P.; Love, C.; Whitby, R.; Roberts, D. A.

Tetrahedron Lett. 1988, 29, 2867. See also: (c) Nicolaou, K. C.; Prasad,

C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335.

(21) Williams, R. M.; Cushing, T. D. Tetrahedron Lett. 1990, 31, 6325.

560 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

Scheme 3^a

^aReagents and conditions: (a) 4.0 equiv of NaOH, 1.0 equiv of 30% H₂O₂, 81-93%; (b) H₂, Pd/C, AcOH, 92%; (c) 2.5 equiv of BBr₃, CH₂Cl₂,

-78 °C, 99%; (d) 1.2 equiv of prenyl bromide, 1.1 equiv of K₂CO₃, DMF, 0 °C to room temperature, 52%; (e) m-CPBA, NaHCO₃, CH₂Cl₂; (f) 1.2

equiv of SnCl₄, THF, 64%; (g) 1.6 equiv of NaBH₄, 3.5 equiv of BF₃‚OEt₂, THF, 44-50%; (h) t-BuMe₂SiCl, im, DMF, 40 °C, 83%; (i) CH₂O,

HNMe₂, AcOH, H₂O, 99%.

resulting from a 1,2 hydride shift.²⁶A number of methods were

explored to effect the dehydration of the secondary alcohol of

dioxepin 28; the best result was realized with methyltriphenoxy-

phosphonium iodide (MTPI) in HMPA to provide 26.²⁷

With a proven method accessible for the construction of the

dioxepin ring system, attention was focused on constructing the

requisite gramine derivative. Oxygenated indoles are notori-

ously unstable and undergo facile autoxidation,²⁸photooxida-

tion,²⁹dimerization, and polymerization.³⁰In light of this

problematic reactivity, our plan called for formation of the

dioxepin ring system prior to indole (gramine) formation. The

approach employed involved the formation of a suitably

substituted oxindole (essentially a protected indole), followed

by the construction of the dioxepin and final elaboration into

the gramine derivative.

explored, but nothing satisfactory was found; it was thus decided

to forgo any protecting group for the 6-hydroxy position.

Oxindole 31 was cleanly demethylated upon treatment with

(clear) boron tribromide. The resulting oxindole 32 was

subjected to the prenylation conditions, and the desired alkylated

product 33 was obtained in 52% yield.^34,35Both of the methods

discussed above for the formation of the seven-membered ring

were examined. The phenylselenoetherification procedure failed

on this substrate, and only products resulting from electrophilic

aromatic substitution were formed.

The alternative epoxidation/Lewis acid-mediated cyclization

again proved to be successful on this substrate. The epoxidation

reaction (m-CPBA) had to be buffered with NaHCO₃, to prevent

the formation of the six-membered-ring tertiary alcohol. In most

cases, the reaction was worked up and taken on to the next

step without purification (the labile epoxide tended to cyclize

to the six-membered tertiary alcohol upon contact with silica

gel). The incipient epoxide product was directly treated with

SnCl₄in THF to provide the desired seven-membered-ring

alcohol 34 (64% overall yield from 33).

The known pyruvic acid 29 (Scheme 3)³¹(prepared in five

steps from vanillin) was oxidatively decarboxylated³²to afford

the phenylacetic acid 30, which was reductively cyclized to give

the required oxindole 31³³in nearly quantitative yield.

At this point, a method was needed to differentiate between

the two phenolic substituents for the prenylation reaction. A

number of attempted selective protecting group strategies were

N-Alkylated oxindoles have been reported to be reduced to

indoles by the use of DIBAL or LiAlH₄;³⁶however, in the case

of unsubstituted oxindoles, this reduction either fails or requires

(26) For a related observation, see: Taylor, S. T.; Davisson, M. E.;

Hissom, B. R., Jr.; Brown, S. J.; Pristach, H. A.; Schramm, S. B.; Harvey,

S. M. J. Org. Chem. 1987, 52, 425.

(27) Hutchins, R. O.; Hutchins, M. G.; Milewski, C. A. J. Org. Chem.

1972, 37, 4191.

(28) Houlihan, W. J.; Remers, W. A.; Brown, R. K. Indoles, Part one,

The Chemistry of Heterocycles; John Wiley & Sons, Inc.: New York, 1972.

(29) (a) Chan, A. C.; Hilliard, P. R., Jr. Tetrahedron Lett. 1989, 30, 6483.

(b) d’Ischia, M.; Prota, G. Tetrahedron 1987, 43, 431.

(30) This difficulty was observed in a short synthesis of the known

6-acetoxy-7-methoxyindole (i). The unstable substance i was treated with

TMSI, producing the dimer ii as the sole product.

(33) This material has interesting chemical and physical characteristics.

The solvent must be removed immediately after the hydrogenolysis to

prevent the white product from turning to a black sludge. This oxindole 31

would also change from a white color to a metallic gray simply by drying

on the vacuum pump. These decomposition properties are no doubt due to

the autoxidation of the indole tautomer form.

(34) The undesired regioisomer was obtained in less than 1% yield, and

the bis-alkylated material was produced in only 8.3% yield. This selectivity

is presumably a manifestation of the domination of inductive effects of the

amide functionality directing the alkylation to the 7-position.

(35) The structure of compound 33 was confirmed by simply tosylating

33 and comparing the product (37) to the same substance prepared from

31. The two independently synthesized products were identical in every

way.

See: (a) Walker, G. N. J. Am. Chem. Soc. 1955, 77, 3844. (b) Burton, H.;

Duffield, J. A.; Prail, P. F. G. J. Chem. Soc. 1950, 1062. (c) Beer, R. J. S.;

Mcgrath, L.; Robertson, A.; Woodier, A. B. J. Chem. Soc. 1949, 2061. (d)

Beer, R. J S.; Clarke, K.; Khorana, H. G.; Robertson, A. J. Chem. Soc.

1948, 2223. (e) Chan, A. C.; Hilliard, P. R., Jr. Tetrahedron Lett. 1989, 30,

6483. (f) d’Ischia, M.; Prota, G. Tetrahedron 1987, 43, 431. (g) Deibel, R.

M. B.; Chedekel, M. R. J. Am. Chem. Soc. 1984, 106, 5884. (h) Heacock,

R. A. Chem. ReV. 1959, 59, 181.

(31) (a) Beer, R. J. S.; Clarke, K.; Davenport, H. F.; Robertson, A. J.

Chem. Soc. 1951, 2029. (b) Bennington, F.; Morin, R. D.; Clark, L. C., Jr.

J. Org. Chem. 1959, 24, 917.

(32) Kosuge, T.; Ishida, H.; Inabe, A.; Nukaya, H. Chem. Pharm. Bull.

1985, 33, 1414.

(36) (a) Kishi, Y.; Nakatsuka, S.; Fukuyama, T.; Havel, M. J. Am. Chem.

Soc. 1973, 95, 6494. (b) Robinson, B. Chem. ReV. 1969, 69, 785.

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 561

Scheme 4^a

a

Reagents and conditions: (a) 36, 0.5 equiv of PBu₃, MeCN, 51%; (b) DMAP, Et₃N, BOC₂O, CH₂Cl₂, 90%; (c) 5 equiv of LiCl, 1.5 equiv of

H₂O, HMPA, 100 °C, 66%; (d) 3.0 equiv of n-Bu₄NF, THF, 79%; (e) 1.9 equiv of LiCl, 4.0 equiv of collidine, 4.0 equiv of MsCl, DMF, 86%; (f)

t-BuMe₂SiOTf, 2,6-lutidine,CH₂Cl₂, 76%; (g) 10 equiv of NaH, benzene, 11%.

Figure 2.

more vigorous conditions. In 1972 it was reported³⁷that

substituted and unsubstituted oxindoles could be reduced to the

corresponding indole in high yields with borane in THF at 0

°C. Oxindole 34 was subjected to these conditions (1.0 M BH₃/

THF, Aldrich), but with no reaction. However, when oxindole

34 was treated with 1.6 equiv of NaBH₄and 3.5 equiv of BF₃‚-

OEt₂in THF for 1 day (0 °C to room temperature), the desired

indole 35 was obtained in 43-50% yield. The indole 35 was

treated with a warm solution of TBDMSCl and imidazole in

DMF, to provide the required O-silylated indole, which was

easily converted to the gramine 36 through the well-known

Mannich procedure (Scheme 3).

Construction of the Bicyclo[2.2.2] Ring System. To probe

the stability of the dioxepin-indole in subsequent transforma-

tions, a model study involving the previously synthesized

racemic piperazinedione 38³⁸was investigated (Scheme 4).

Indole 36 was condensed with the piperazinedione 38 following

the Somei/Kametani conditions¹⁸to give the desired syn product

39 (a racemic mixture of two diastereomers) in 51% yield. The

relative stereochemistry of this substance was evident by an

examination of the ¹H NMR spectrum. There is a large upfield

shift of the proline ring protons of 39 (δ Ha, Hb, Hc; 0.03-

0.19 (m), 0.43-0.52 (m), 0.62-0.72 (m) ppm). It is well-

known that N-alkylated piperazinediones prefer to adopt a boat-

like conformation due to the planar geometry of the amides and

A-1,3 steric interactions of N-alkyl residues. This forces the

substituents on the amino acid R-carbons to adopt either

pseudoaxial or pseudoequatorial dispositions. In conformer B

(Figure 2) the carbomethoxy group is sterically congested by

the bulky isopentenyl group, favoring the alternate boat

conformer (A), which positions the indole ring under the

piperazinedione, positioning the two pyrrolidine protons Ha and

Hb directly over the shielding cone of the aromatic indole ring

system; the corresponding anti-isomer cannot adopt this type

of conformation. Furthermore, a consideration of the mecha-

nism of the Somei/Kametani reaction¹⁸supports the expectation

that the syn-isomer (39) should be the major product. The

gramine derivative (36) reacts with tributylphosphine to form

a bulky (tributylphosphino)indole intermediate that can only

approach from the less congested face of the piperazinedione

enolate, away from the isopentenyl moiety.

A similar phenomenon was observed when 39 was subjected

to the decarbomethoxylation procedure (LiCl, H₂O, HMPA)

directly. The two main products isolated were the syn-isomer

40 and the anti-isomer 41, in a ratio of 3.3:1.0 (Figure 3). These

1

stereochemical assignments were made by comparing the H

NMR spectral data of 40 and 41. There was a pronounced

upfield shift of three pyrrolidine ring protons in compound 41,

a shift that is not observed for diastereomer 40.

Piperazinedione 39 was first converted to the BOC-protected

indole 42, which was subsequently subjected to a decar-

bomethoxylation reaction supplying the syn-diastereomer 43 as

(37) Sirowej, H.; Khan, S. A.; Plieninger, H. Synthesis 1972, 84.

(38) Williams, R. M.; Glinka, T. Tetrahedron Lett. 1986, 27, 3581.

562 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

Figure 3.

Scheme 5^a

^aReagents and conditions: (a) 3.8 equiv of CAN (0.33 M), 2:1 CH₃CN/H₂O, 2 h, 79%; (b) (i) 2 equiv of NaBH₄, EtOH; (ii) t-BuPh₂SiCl, im,

DMF, 75%; (c) (i) 1.0 equiv of n-BuLi, 1.1 equiv of MeOCOCl, -78 °C; (ii) 2.2 equiv of LiN(SiMe₃)₂, 1.1 equiv of MeOCOCl, THF, -100 °C,

93%; (d) 36, 0.5 equiv of PBu₃, CH₃CN, reflux, 73%; (e) LiCl, HMPA, 100 °C (syn/anti 3:1), 89%; (f) Me₃OBF₄, Na₂CO₃, CH₂Cl₂(syn, 81%; anti,

62-71%); (g) (i) BOC₂O, DMAP, Et₃N, CH₂Cl₂; (ii) n-Bu₄NF, THF (syn, 90%; anti, 85%); (h) NCS, Me₂S (syn, 74-81%; anti, 86%).

the major product. Compound 43 (the minor, anti-diastereomer

was not utilized) was desilylated to provide the diol 44, which

was converted to the allylic chloride 45. Careful treatment of

45 with t-BuMe₂SiOTf, to prevent transesterification of the BOC

groups,³⁹gave the desired product 46 in 76% yield. Allylic

chloride 46 was subjected to 10 equiv of NaH in refluxing

benzene, but the reaction proved extremely sluggish. After 5

days, the desired product 47 was obtained in a poor 11% yield

(19% based on recovered 46; accompanied by extensive

decomposition). The syn-isomer 47 was the only stereoisomer

formed in this reaction; the corresponding anti-isomer was not

detected. While this reaction demonstrated the potential viability

of the stereoselective intramolecular S_N2′ reaction, work on the

racemic model system was halted, due to the low yield in this

key transformation coupled with perceived difficulties associated

with removing the N-p-methoxybenzyl group.

Total Synthesis of (+)-Paraherquamide B. Starting from

the known piperazinedione 48 (prepared in eight steps from (S)-

proline),¹¹the enal 49 was obtained in 79% yield by treatment

of 48 with a 0.33 M solution of ceric ammonium nitrate (Scheme

5).⁴⁰The resulting product (49) was reduced with NaBH₄and

protected with t-BuPh₂SiCl in a two-step process to give the

silyl ether 50 in 75% yield. Compound 50 was then subjected

to a two-step, one-pot acylation providing the required substrate

51 in 93% yield. The crude material was a mixture of epimers

in a ratio of approximately 4:1 (syn:anti). Interestingly this

mixture had a tendency to epimerize during column chroma-

(40) Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto, H. Chem. Lett.

1983, 1001.

(39) Sakaitani, M.; Ohfune, Y. J. Am. Chem. Soc. 1990, 112, 1150.

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 563

Figure 4.

Scheme 6

tography, resulting in an increase in the proportion of the syn-

isomer. The two products were combined and condensed with

the gramine 36 providing the indole 52 in 73% yield as a mixture

of two diastereomers (epimeric at the secondary alcohol

stereogenic center). Interestingly, the imidic carbamate group

was also cleaved in the course of this reaction. Compound 52

was subjected to the decarbomethoxylation procedure, affording

a 3:1 mixture of 53 (syn) and 54 (anti) in 89% combined yield.

solution of 58 and Me₂NH in CH₃CN furnished compound 59

in 92% yield⁴³(Scheme 7).

The strategy planned for the reduction of the tertiary amide

called for the protection of the secondary lactam as a lactim

ether,⁴⁴and this group seemed suitable for use earlier in the

synthesis and appeared compatible with the S_N2′ cyclization.

Thus, syn-isomer 53 was treated with 20 equiv (optimum) of

Na₂CO₃and 5 equiv of Me₃OBF₄in dichloromethane for 4 h,

to yield 81% of compound 60. Even though the next two

reactions could be carried out in a stepwise fashion, it proved

most convenient to convert 60 directly to the protected diol 62

in a one-pot, two-step sequence. Diol 62 was then subjected

to the chlorination procedure successfully used in the conversion

of diol 44 to the allylic chloride 45. Unfortunately, under these

conditions, the reaction failed and the lactim ether was cleanly

deblocked back to the lactam. This problem was finally solved

by following the procedure of Corey,⁴⁵which called for the

addition of compound 62 to a mixture of N-chlorosuccinimide

and dimethyl sulfide, which yielded the chloride 64 in 81%

yield.

The lactam 53 could be converted to the N-BOC-protected

allylic chloride 55 in four steps and in good overall yield

(Scheme 6), but numerous attempts to effect the S_N2′ reaction

on this substrate failed. These reactions were capricious and

were accompanied by the occasional appearance of the spiro-

lactones 56 and 57, formed in low yield <5% (Figure 4). It

seems likely that the failure of 55 to cyclize in the desired

fashion can be attributed to nonbonding interactions between

the tert-butoxycarbonyl group and the pendant dioxepin in-

dole.^41,42

These observations dictated that a suitable amide protecting

group would have to be selected that was less electron

withdrawing and less sterically demanding than both the tert-

butoxycarbonyl and the p-methoxybenzyl groups. The loss of

the lactam methoxycarbonyl group in the alkylation of 51 with

the gramine 36 was presumably due to N f N acyl transfer to

dimethylamine, a byproduct of the Somei/Kametani reaction.

This appears to be a general reaction that was used to selectively

deprotect the N-tert-butoxycarbonyl group of 58 without de-

blocking the N-tert-BOC-protected indole. Thus, refluxing a

Allylic chloride 64 was reprotected with t-BuPh₂SiOTf to

provide 66 in 77-82% yield. The stage was now set to effect

the S_N2′ reaction. Compound 66 was refluxed in benzene with

20 equiv of sodium hydride, resulting in a very clean and high-

yielding cyclization reaction furnishing the desired product 68

in 93% yield (Scheme 8).

(43) This result is noteworthy, especially in light of a report that tert-

butoxycarbonyl-protected amides are cleaved to the tert-butoxycarbonyl-

protected amines with DEAEA (2-(N,N-diethylamino)ethylamine) in CH₃CN

at room temperature; see: Grehn, L.; Gummarsonn, K.; Ragnarsson, U.

Acta Chem. Scand. B 1987, 41, 18. However, the substrates examined in

that report were all open-chain amides. Interestingly it is known that BOC-

protected lactams can be cleaved by base but it is the amide bond that is

broken as was observed on substrate 55. Recently it has been reported that

Mg(OMe)₂will also cleave lactam carbamates including BOC-protected

lactams; see: Wei, Z.-Y.; Knaus, E. E.; Tetrahedron Lett. 1994, 35, 847.

(44) Williams, R. M.; Brunner, E. J.; Sabol, M. R. Synthesis 1988, 963.

(45) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13,

4339.

(41) The formation of the two spiro compounds 56 and 57 is presumably

due to the increased electrophilicity of the N-acylated amide. Apparently,

trace moisture in the reaction mixture caused the production of hydroxide,

which then hydrolyzed the reactive amide bond. The resulting carboxylic

acid cyclized in an S_N2′ fashion, furnishing the spiro lactones.

(42) (a) Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem.

1989, 54, 228. (b) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem.

1983, 48, 2424.

564 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

Scheme 7

Scheme 8

This last series of reactions was also carried out in parallel

on the anti-isomer 54. Following the same sequence (five steps)

we obtained the fully protected chloride 67 in good yield. The

chloride 67 was then refluxed in benzene with the required

amount of sodium hydride to yield the same product (68, 85%

yield) as that obtained from 66. The yields of 68 from both

routes were very high, and the undesired anti-diastereomer was

not detected. The high degree of facial selectivity observed in

the cyclizations to 68 and 47 is quite interesting and warrants

some comments. It is generally accepted that S_N2′ reactions

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 565

Figure 5.

favor a syn orientation⁴⁶(i.e., the incoming nucleophile attacks

the π-electrons from the same face as the departing leaving

group, polarizing the π-system in the proper orientation for a

“backside” displacement on the C-Cl bond). Alternatively, a

frontier molecular orbital analysis has indicated^46athat the

stabilization imparted by a HOMO_Nuc-LUMO_allylicinteraction

is greater for the syn overlap. While the greatest level of

diastereoselectivity was observed with a nonpolar aprotic solvent

(benzene), a fairly significant change in the relative amounts

of the syn- and anti-diastereomers can be realized by simply

changing the solvent to a more polar solvent such as DMF.¹¹In

the present system, additional stabilization for the endo transition

state may be due to the formation of a tight contact ion pair

between the chlorine atom and sodium atom of the enolate

species (see A, Scheme 8) in the transition state for the formation

of the C-C bond.⁴⁷The poor ligating solvent benzene is not

capable of effectively solvating the enolate cation nor the

developing chloride anion in the transition state. It is reasonable

that this type of association favors the rotamer that positions

the allylic chloride moiety over the enolate, resulting in the

desired syn stereochemistry.

With the bicyclo[2.2.2] ring system constructed in a reliable

and high-yielding sequence, attention was turned to the final

C-C bond-forming reaction on the indole. Due to the strongly

acidic conditions that were used previously for a related

cyclization reaction in the brevianamide synthesis, it was

assumed that the silyl ether, the tert-butoxycarbonyl protecting

group, and the lactim ether would be removed during this

cyclization reaction. Subjecting compound 68 to the standard

conditions (dilute, aqueous HCl in dioxane at 10 °C)^11,19,48

resulted in extensive decomposition, and none of the desired

cyclized product was ever detected. The reaction conditions

were extensively varied using different acids and temperatures,

but the only recognizable products were those stemming from

the loss of protecting groups. The problem might be attributed

to the enhanced basicity of the indole at the 2-position (indole

numbering) caused by the electron-donating oxygen atoms in

the aromatic ring. If protonation at the 2-position is kinetically

competitive with olefin protonation, cyclization would be

precluded.

Heck-type cyclialkylations of various isoquinuclidine model

compounds. Compound 68 was exposed to these conditions,

affording the heptacycle 69 in 63-82% yields. During the

course of the reaction, the lactim ether moiety was cleaved,

restoring the free, secondary amide.⁵⁰The main byproduct of

this reaction was the uncyclized free lactam 68a (Figure 5),

which curiously did not cyclize to 69 when subjected to the

same conditions. It was also observed that the lactim ether

protected heptacycle 71 could not be deblocked to the free

lactam 69 with PdCl₂and AgBF₄alone, implying that the

cleavage of the lactim ether is due to the tetrafluoroboric acid

produced in the cyclization, and that the cyclization occurs prior

to lactim ether cleavage.

Trost and Fortunak speculated⁴⁹that the cyclization mecha-

nism was either a Heck-type arylation or the electrophilic

aromatic substitution of a palladium-complexed olefin, and there

was evidence to support both mechanistic possibilities. It is

possible that the palladium chloride and the silver tetrafluo-

roborate react to form a powerful Lewis acid, since an incubation

period involving these two reagents is needed prior to the

introduction of the substrate. It was reported⁴⁹that there is no

reaction with other mixed-metal systems involving palladium

chloride (e.g., boron trifluoride, aluminum chloride, stannous

chloride, stannic chloride, titanium trichloride). The enhanced

basicity (nucleophilicity) at the 2-position of indole 68 renders

this substance perfectly disposed to undergo a Heck-type

arylation reaction.

There are several reports of methods that will selectively

reduce a tertiary amide in the presence of a secondary amide.⁵¹

The secondary lactam of 69 was protected as the lactim ether

71 and treated with diborane; however, the spectral character-

istics of the major products isolated were consistent with

reduction of both the tertiary amide and the lactim ether. In

1991 Martin et al.⁵²successfully used alane to reduce a tertiary

amide in the presence of an oxindole (secondary amide) relying

on the known rate difference for reduction between these two

groups.⁵³However, initial experiments with this reagent gave

poor results, with the secondary amide undergoing reduction

along with the tertiary amide. Compound 69 (and 71) is

sufficiently twisted such that the gem-dimethyl groups ef-

fectively block the â-face of the tertiary amide (Figure 6),

A search of the literature revealed a 1982 Trost and Fortunak

paper⁴⁹wherein PdCl₂and AgBF₄were utilized to effect the

(50) (a) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571.

(b) Karabelas, K.; Westerlund, C.; Hallberg, A. J. Org. Chem. 1985, 50,

3896. (c) Cava, M. P.; Kevinson, M. I. Tetrahedron 1985, 41, 5061 and

literature cited therein.

(51) In a recently reported synthesis of gelsemine, a tertiary lactam was

reduced in the presence of a secondary lactam with DIBAH. However, this

reagent failed on substrates 69; see: Dutton, J. K.; Steel, R. W.; Tasker, A.

S.; Popsavin, V.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994,

765.

(46) (a) Magid, R. M.; Fruchey, O. S.; Johnson, W. L.; Allen, T. G. J.

Org. Chem. 1979, 44, 359. (b) Magid, R. A. Tetrahedron 1980, 36, 1901.

(47) The idea that the stereochemical outcome of an intramolecular

enolate alkylation is determined by chelation in the transition state was

recently demonstrated by Denmark and Henke, who observed a marked

preference for a “closed” transition state (coordination of the cationic

counterion to an enolate and the developing alcohol) resulting in a syn

product. For example, the highest syn:anti ratio (89:11) was obtained in

toluene and the lowest syn:anti ratio (2:98) was obtained with a crown

ether. These observations parallel the facial selectivities described herein

and in ref 11 on the intramolecular S_N2′ reaction; see: (a) Denmark, S. A.;

Henke, B. R. J. Am. Chem. Soc. 1991, 113, 2177. (b) Denmark, S. A.;

Henke, B. R. J. Am. Chem. Soc. 1989, 111, 8022.

(52) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore,

M. J. Am. Chem. Soc. 1991, 113, 6161.

(53) (a) Yoon, N. M.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 2927.

(b) Marlett, E. M.; Park, W. S.; J. Org. Chem. 1990, 55, 2968. (c) Jorgenson,

M. J. Tetrahedron Lett. 1962, 559. (d) Another very recent synthesis of

gelsemine reported the reduction of the same gelsemine precursor (as in

ref 51) with AlH₃. Newcombe, N. J.; Fang, Y.; Vijn, R. J.; Hiemstra, H.;

Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767.

(48) (a) Hutchison, A. J.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 6786.

(b) Guller, R.; Borschberg, H.-J. Tetrahedron Lett 1994, 35, 865.

(49) Trost, B. M.; Fortunak, J. M. D. Organometallics 1982, 1, 7.

566 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

rangement before the amide reduction step was investigated.

Thus, piperazinedione 69 was readily deblocked with TFA to

provide the amide 76 in 95% yield (Scheme 10). This substance

was treated with t-BuOCl and Et₃N in the same manner as

before, producing two products 77/78 (≈1:4 ratio). Using a

milder MeOH/H₂O/AcOH system (stirring at room temperature),

an oxindole compound 79 was formed in 29% yield. Although

this result was encouraging, this substance appeared to possess

the incorrect relative stereochemistry at the spiro-ring juncture.

1

This assignment was supported by comparing the H NMR

spectra of 79 and an authentic sample of (-)-paraherquamide

B (1). The gem-dimethyl signals of 79 were shifted upfield,

indicating that one methyl group is in the shielding cone of the

oxindole carbonyl.

Figure 6.

leaving the R-face relatively unencumbered. However, a

modification of the alane procedure⁵²proved satisfactory for

this transformation. The piperazinedione 69 was pretreated with

AlEt₃, with the expectation that this Lewis acid would form a

complex with the more exposed secondary lactam (69a, Figure

6) and leave the tertiary lactam accessible for reduction.

Following 10 min of precomplexation with AlEt₃, 5 equiv

of AlH₃-Me₂NEt complex was added, followed by quenching

with NaCNBH₃, acetic acid, and methanol to provide the desired

amine 70 in 63% yield. Compound 70 was smoothly alkylated

with methyl iodide, affording the N-methylated product 72 in

95-98% yield. Compound 72 was subsequently deblocked with

80 equiv of TFA in CH₂Cl₂to yield the penultimate heptacycle

73 in 97% (Scheme 9).

After a careful reexamination of the decomposition products

obtained from the attempted pinacol-type rearrangement of 73,

it was determined that there were mainly two decomposition

pathways, and that they were in direct competition with the

desired process. These two pathways involve the intermediacy

of an oxonium-stabilized tertiary carbocation (at C-3 of the

indole) that decomposes to quinone-type products. Additionally,

products were isolated whose spectral characteristics were

consistent with an elimination process followed by nucleophilic

reaction with the solvent at the tryptophan benzylic carbon.

In the classical pinacol rearrangement there is a distinct

carbonium ion intermediate, but recent studies have shown that

this may in fact be more of a concerted process⁵⁷and,

furthermore, that the nature of the solvent can have an impact

on which of the two processes, concerted or stepwise, will

predominate. There have been conflicting reports in the

literature on whether this type of rearrangement is, at all times,

stereospecific.^58,59A detailed study^59cinvolving the isolation

and separation of the two diastereomeric chloroindolenines

derived from yohimbine demonstrated that this reaction can be

entirely stereospecific. Alternatively, by increasing the solvating

power of the reaction medium, each of these chloroindolenines

formed two rearranged products, indicating that the reaction

went (at least in part) by way of a carbocationic intermediate.

This is consistent with the observed production of 79 from 77

and 78. A less polar solvent system should minimize the side

reactions involving carbocation intermediates and, at the same

time, should increase the stereospecific nature of the pinacol-

type rearrangement. Thus, treatment of 73 with t-BuOCl and

Et₃N in CH₂Cl₂provided the two chloroindolenines 74 and 75

(≈2.25:1 ratio, respectively). The solvent was removed, and

the crude reaction mixture was refluxed with a solution of 95%

THF, 4% H₂O, and 1% TFA, giving a 62% yield of oxindole

products (43% of the desired 80 and 19% the epi product 81).⁶⁰

The C-3-epi-isomer (81) was easily distinguishable from the

desired isomer (80) by the upfield shift of the gem-dimethyl

The stage was now set for the final transformations involving

the oxidative pinacol-type rearrangement and dehydration. Due

to the difficulties encountered in the attempted cationic cycliza-

tion on the indole (cf. 68 f 69), there was concern about the

reactivity of the indole ring toward the electrophilic reagents

that would be utilized in the oxidative pinacol-type reaction.

There was the possibility that the electron-donating oxygen

atoms on the indole ring would hinder the acid-catalyzed

rearrangement of, for example, an intermediate chloroindole-

nine,⁵⁴similarly to the way that strong acid hindered the cationic

cyclization.⁵⁵When compound 73 was treated with tert-butyl

hypochlorite and triethylamine, there was an almost an instan-

taneous reaction resulting in the total disappearance of starting

material and the appearance of two new components (≈1:2 ratio

1

as evidenced by H NMR analysis) that were presumed to be

the expected diastereomeric chloroindolenines. When this

mixture was subjected to the standard rearrangement procedure

employing a refluxing solution of acetic acid, water, and

methanol, these substances slowly decomposed (many bands

in the PTLC).⁵⁶

Since the tertiary amine of 73 might react with the chlorinat-

ing reagent and was thus considered to be a possible culprit in

these oxidations, an attempt to effect the pinacol-type rear-

1

signals in the H NMR spectrum. The relative amounts of

(54) (a) Gaskell, A. J.; Radunz, H. -E.; Winterfeldt, E. Tetrahedron Lett.

1970, 5361. (b) Winterfeldt, E.; Gaskell, A. J.; Korth, T.; Radnuz, H.-E.;

Walkowiak, M. Chem. Ber. 1969, 102, 3558. (c) Hollinshead, S. P.;

Grubisha, D. S.; Bennett, D. W.; Cook, J. M. Heterocycles 1989, 29, 529.

(55) Concern about this possible difficulty was somewhat ameliorated

by the knowledge of an alternative procedure that employed OsO₄-pyridine.

See: (a) Takayama, H.; Kitajima, M.; Ogata, K.; Sakai, S. J. Org. Chem.

1992, 57, 4583. (b) Takayama, H.; Odaka, H.; Aimi, N.; Sakai, S.

Tetrahedron Lett. 1990, 38, 5483. (c) Takayama, H.; Masubuchi, K.;

Kitajima, M.; Aimi, N.; Sakai, S. Tetrahedron 1989, 45, 1327. (d) Fu, X.;

Cook, J. M. J. Org. Chem. 1993, 58, 661. See also: (e) Takayama, H.;

Tominaga, Y.; Kitajima, M.; Aimi, N.; Sakai, S. J. Org. Chem. 1994, 59,

4381.

products (80 and 81) indicate that the cyclization was stereospe-

cific under these conditions. It was thus deduced that an

increase in the ratio of the desired oxindole 80 to the undesired

(57) Osamura, Y.; Nakamura, K. J. Am. Chem. Soc. 1993, 115, 9112.

(58) Parker, A. J. Chem. ReV. 1969, 69, 1.

(59) (a) Owellen, R. J.; Hartke, C. J. Org. Chem. 1976, 41, 102. (b)

Kuehne, M. E.; Roland, D. M.; Hafter, R. J. Org. Chem. 1978, 43, 3703.

(c) Awang, D. V. C.; Vincent, A.; Kidack, D. Can. J. Chem. 1984, 62,

2667.

(60)

(56) Similar problems were observed during the total synthesis of

isopteropodine and pteropodine; see: Martin, S. F.; Mortimore, M.

Tetrahedron Lett. 1990, 31, 4557. In this system, the solution involved

treating the chloroindolenines with silver perchlorate in methanolic per-

chloric acid. This method was attempted on substrate 73, but unfortunately

it failed to produce any desired product.

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 567

Scheme 9^a

^aReagents and conditions: (a) PdCl₂, AgBF₄, MeCN; (b) NaBH₄(63-82% from 68); (c) 1.1 equiv of Et₃Al, 5.0 equiv of AlH₃-DMEA, THF,

toluene; (d) 2.0 equiv of NaCNBH₃, AcOH, MeOH (65% from 69); (e) 2.5 equiv of NaH, 2.0 equiv of MeI, DMF (98%); (f) 80 equiv of TFA,

CH₂Cl₂(96%); (g) t-BuOCl, pyridine, -15 °C; (h) 90% THF, 10% H₂O, pTsOH (76%); (i) MTPI, DMPU (79%).

Scheme 10

Scheme 11

isomer 81 could be achieved simply by finding a method that

would increase the ratio of chloroindolenines (74:75). The

R-face of 73 is considerably more hindered than the â-face, a

supposition that was supported by the difficulties encountered

in the reduction of 71 and 69. Increasing the steric bulk of the

chlorinating agent should favor attack on the â-face of 73, thus

568 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

convergent, starting from (S)-proline and vanillin with an overall

yield of 1.4% from (S)-proline.

Key features of this synthesis include (1) a new method to

effect reduction of unprotected oxindoles to indoles; (2) a

complex application of the Somei/Kametani reaction that

concomitantly effected a desired decarbomethoxylation; (3) a

high-yielding and entirely stereocontrolled intramolecular S_N2′

cyclization reaction; (4) a mild Pd(II)-mediated cyclization

reaction that concomitantly deblocked a lactim ether protecting

group; and (5) the chemoselective reduction of a highly hindered

tertiary lactam in the presence of an unhindered secondary

lactam, utilizing precoordination of the more reactive secondary

lactam to triethylaluminum.

Experimental Section

General information. Melting points were determined in open-

ended capillary tubes and are uncorrected. ¹H and ¹³C NMR spectra

were recorded on either a Bruker WP-270SY 270 MHz or a Bruker

AC300P 300 MHz NMR spectrometer. Chemical shifts are reported

in ppm relative to CHCl₃at δ 7.24 or TMS at δ 0.0. IR spectra were

recorded on a Perkin-Elmer 1600 FT IR spectrometer. Mass spectra

were obtained on a V. G. Micromass Ltd. Model 16F spectrometer.

The CD spectrum was obtained on a Jasco J710 spectropolarimeter.

High-resolution mass spectra were obtained from the Midwest Center

for Mass Spectrometry Department of Chemistry, University of

NebraskasLincoln, Lincoln, NE. Elemental analyses were obtained

from M-H-W Laboratories, Phoenix, AZ. Optical rotations were

recorded on a Perkin-Elmer 24 polarimeter at a wavelength of 589 nm

using a 1.0 dm cell of 1.0 mL total volume.

Column chromatography and flash column chromatography were

performed with silica gel grade 60 (230-400 mesh). Radial chroma-

tography was performed with a Harrison Research Chromatotron Model

7924 using E. Merck silica gel 60 PF-254 containing gypsum; 1, 2, 4,

and 8 mm plates were used as needed. Preparatory thin layer

chromatography (PTLC) was carried out with Merck Kieselgel 60 F₂₅₄

precoated glass plates (either 0.25 or 0.50 mm); visualization was carried

out with ultraviolet light and/or heating with a solution of 5-7%

phosphomolybdic acid; staining with I₂; vanillin; or Dragendorf.

All solvents were commercial grade and were distilled and dried as

follows: tetrahydrofuran (THF) from sodium benzophenone ketyl;

diethyl ether from sodium benzophenone ketyl; carbon tetrachloride

from calcium hydride; dioxane from sodium; benzene from sodium

benzophenone ketyl; dichloromethane from calcium hydride; acetonitrile

from P₂O_5.DMF was dried and stored over 3 Å molecular sieves, as

were benzene and toluene. HMPA was dried and stored over 4 Å

molecular sieves. Dimethyl sulfide, 2,6-lutidine, triethylamine, and

pyridine were all distilled prior to use. Phenylselenium chloride was

purified by sublimation. N-Chlorosuccinimide (NCS) was recrystallized

from benzene. LiCl was dried and stored in the oven. All other

reagents were commercial grade and used without further treatment.

Abbreviations are used throughout: N,N-dimethylformamide (DMF);

acetic acid (AcOH); di-tert-butyl dicarbonate ((BOC)₂O); methyltriph-

enoxyphosphonium iodide (MTPI); ethyl acetate (EtOAc); m-chlorop-

erbenzoic acid (m-CPBA); (N,N-dimethylamino)pyridine (DMAP);

hexamethylphosphoramide (HMPA); ceric ammonium nitrate (CAN);

methanesulfonyl chloride (MsCl); N-chlorosuccinimide (NCS); trif-

luoroacetic acid (TFA); dimethylethylamine (DMEA); imidazole (im);

1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).

Figure 7.

providing a greater relative amount of chloroindolenine 74.

When 73 was treated with t-BuOCl in pyridine instead of

triethylamine, the desired chloroindolenine 74 was produced in

a much more stereoselective fashion. It can be speculated that

tert-butyl hypochlorite forms a bulky complex with pyridine,

delivering the chlorine more selectively to the least hindered

R-face of 73 (only a small amount, ≈5%, of the undesired

isomer 75 was formed under these conditions (Scheme 11)).

Employing a minor modification of the solvent system, the

crude mixture of 74/75 was refluxed with a solution of 90%

tetrahydrofuran, 10% H₂O containing 15 equiv of p-toluene-

sulfonic acid to give the desired oxindole 80 in 76% yield (from

73), with only 4% of the undesired 81 being formed.

The stereospecific conversion of the chloroindolenines into

the corresponding oxindoles requires that the water molecule

attack the imine from the same face as the chlorine atom. Anti

attack on the imine is not as likely because of certain

stereoelectronic effects.^59cThe addition of water to the â-face

of 74 situates the six-membered ring adjacent to the indole ring

in a stable chair conformation that would also place the C-Cl

bond and the migrating (CH₃)₂CC group in an unfavorable syn

alignment. Conversely, the addition of water to the R-face of

compound 75 would result in an unfavorable boat conformation

that would also place the C-Cl bond and the migrating (CH₃)₂-

CC group in an unfavorable syn alignment. Thus, the major

isomer 74 must either (1) suffer kinetically controlled attack

by water on the same face of 74 as the chlorine atom, which

aligns the migrating group and the C-Cl bond in a stereoelec-

tronically favorable anti orientation, or (2) undergo reversible

attack by water from either face, with only the correct

carbinolamine, which aligns the migrating group and the C-Cl

bond in a stereoelectronically favorable anti orientation, rear-

ranging irreversibly to the oxindole.

The final dehydration reaction (MTPI, DMPU, 18 h) on the

alcohol 80 produced (+)-paraherquamide B (12) in 79% yield

(Scheme 9). This substance proved to be identical to the natural

product by comparison of the ¹H and ¹³C NMR spectra, mobility

on TLC, IR spectra, mass spectra, and UV spectra. Comparison

of the CD spectra of the natural (-)-paraherquamide B (2) and

the synthetic (+)-paraherquamide B (12) (Figure 7) confirmed

the expected enantiomeric relationship between these two

products.

2-[(3-Methyl-2-butenyl)oxy]phenol (24). To a stirred, cold (0 °C),

dark solution of catechol (2.07 g, 18.8 mmol, 5.0 equiv) in DMF (65

mL) in a reaction vessel that had been flushed with Ar was added

anhydrous K₂CO₃(0.520 g, 3.76 mmol, 1.0 equiv). After 5 min, prenyl

bromide (0.441 mL, 3.76 mmol, 1.0 equiv) was added dropwise. The

reaction mixture was kept at 0 °C for ∼6 h and stirred at room

temperature for an additional 18 h. The mixture was then poured into

a separatory funnel, diluted with H₂O (100 mL), and extracted five

times with CH₂Cl₂. The organic layer was washed with brine, dried

over MgSO₄, and evaporated to dryness. The residue was purified by

radial chromatography (eluted with 1% ethyl acetate/hexanes) to give

479 mg (71%) of 24 as a colorless oil. An analytical sample was

obtained by PTLC on silica gel (eluted with hexanes).

Conclusion

The first stereocontrolled, asymmetric total synthesis of (+)-

paraherquamide B has been completed. The synthesis is

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 569

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.74 (3H, s), 1.80 (3H, s),

4.57 (2H, d, J ) 6.8 Hz), 5.49 (1H, m), 5.70 (1H, s, D₂O exch), 6.82-

6.92 (4H, m). IR (NaCl, neat): 3533, 2932, 1612, 1502, 1467, 1385,

1259, 1221, 1106, 997, 743 cm^-1. Mass spectrum (EI): m/e (relative

intensity) 178 (11), 161 (11), 110 (78), 69 (67), 32 (100). Microanalysis

calcd for C₁₁H₁₄O₂: C, 74.13; H, 7.92 Found: C, 73.88; H, 8.00.

MgSO₄, and evaporated to dryness. The crude product was purified

by radial chromatography (eluted with 1:7 EtOAc/hexanes) to afford

842 mg (60% or 59% for two steps) of 28 as an oil. An analytical

sample was obtained by PTLC (eluted with 5:1 EtOAc/hexanes, and

then distilled under reduced pressure).

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.20 (3H, s), 1.53 (3H, s),

2.96 (1H, d, J ) 11.3 Hz, D₂O exch), 3.58 (1H, ddd, J ) 1.1, 4.0, 11.3

Hz), 4.08 (1H, dd, J ) 1.1, 12.6 Hz), 4.20 (1H, dd, J ) 4.0, 12.6 Hz),

6.98-7.02 (4H, m). IR (NaCl, neat): 3448, 2978, 1596, 1490, 1261

cm^-1. Mass spectrum (EI): m/e (relative intensity) 194 (41), 176 (19),

136 (57), 121 (100), 59 (63). HRMS (EI) m/e 194.0943 (C₁₁H₁₄O₃

requires 194.0943).

(()-3,4-Dihydro-2,2-dimethyl-3-(phenylseleno)-2H-benzodiox-

epin (25). A solution of phenylselenium chloride (117.8 mg, 0.615

mmol, 1.05 equiv) in EtOAc (4.1 mL, 0.15 M) was slowly added (∼1

mmol/h) to a stirred solution of 24 (104.4 mg, 0.58 mmol, 1.0 equiv)

in EtOAc (3.90 mL, 0.15 M) at -75 °C under Ar. This mixture was

allowed to warm to room temperature and was stirred for a total of 17

h. The solution was poured into a separatory funnel and washed twice

with H₂O and once with brine. The organic layer was dried over

MgSO₄and evaporated to dryness. The residue was purified by PTLC

(eluted with 1:3 hexanes/benzene) to afford 62.1 mg (32%) of 25. An

analytical sample was obtained by PTLC (eluted with hexanes, and

then distilled under reduced pressure).

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.28 (3H, s), 1.76 (3H, s),

3.62 (1H, dd, J ) 3.4, 10.3 Hz), 4.17 (1H, dd, J ) 10.3, 12.6 Hz),

4.40 (1H, dd, J ) 3.5, 12.6 Hz), 6.94-6.98 (4H, m), 7.30-7.34 (3H,

m), 7.59-7.62 (2H, m). IR (NaCl, neat): 2986, 1491, 1256, 1088,

1000 cm^-1. HRMS (EI): m/e 334.0473 (C₁₇H₁₈O₂Se requires 334.0472).

4-Hydroxy-3-methoxy-2-nitrophenylacetic Acid (30). To a flask

containing 29 (101 g, 397 mmol, 1.0 equiv) at 0 °C was added a solution

of NaOH (63.5 g, 1.59 mol, 4.0 equiv) in H₂O (1.4 L). After 10 min,

hydrogen peroxide (49.5 mL, 437 mmol, 1.1 equiv, 30% solution in

water) was added dropwise. The deep purple solution slowly turned

brown during the addition. The mixture was allowed to reach room

temperature and stirred for 24 h. The reaction mixture was then

acidified with concentrated HCl until pH ≈ 3, during which CO₂was

released and a fine yellow crystalline product precipitated. The mixture

was filtered, washed with cold H₂O, and dried to yield 72.6 g (81%)

of 30. An analytical sample was recrystallized from H₂O to give bright

yellow needles, mp 161-162 °C (when the reaction was carried out

with 11.9 g of the phenylacetic acid, the yield was 93%).

¹H NMR (300 MHz) (acetone-d₆): δ TMS 2.83 (2H, br s, D₂O exch),

3.62 (2H,s), 3.91 (3H, s), 7.10 (2H, s). IR (KBr): 3488, 2958, 2641,

1668, 1533, 1399, 1344, 1296, 1225, 1051, 825 cm^-1. Mass spectrum

(EI): m/e (relative intensity) 228 (M⁺, 0.7), 227 (5.8), 166 (10.0), 106

(13.6), 44 (100). Microanal. Calcd for C₉H₉NO₆: C, 47.58; H, 3.99;

N, 6.16. Found: C, 47.56; H, 4.06; N, 6.25.

2,2-Dimethyl-2H-1,5-benzodioxepin (26). To a stirred solution of

25 (61.7 mg, 0.185 mmol, 1.0 equiv) in THF (3 mL) was added H₂O₂

(0.21 mL, 0.5 mmol, 10 equiv) at 0 °C. The resulting solution was

stirred for 0.5 h and then brought to reflux temperature for 0.5 h. The

mixture was poured into a separatory funnel, diluted with water, and

extracted with ether. The ethereal solution was washed with brine,

dried over MgSO₄, and evaporated to dryness. The residue was purified

by PTLC (eluted with 1:3 hexanes/EtOAc) to afford 16.0 mg (49%) of

26 as a pale yellow oil (see data below).

1,3-Dihydro-6-hydroxy-7-methoxy-2H-indol-2-one (31). A mix-

ture of 30 (23.0 g, 101 mmol, 1.0 equiv) in glacial acetic acid (100

mL) and Pd/C (10%, 1.5 g) was hydrogenated at 40 psi of H₂in an oil

bath (80 °C) for 5 h. The mixture was immediately filtered through a

Celite plug and washed with a small amount of warm AcOH. The

flask was kept under suction (cold) until a large quantity of white

product had precipitated. This was filtered to collect the product, when

an additional quantity of product precipitated under suction. This was

collected, and the two crops of white flakes were combined and dried

under reduced pressure to yield 17.2 g (95%) of 31. An analytical

sample was recrystallized from H₂O to give white crystals, mp 210-

211 °C.

¹H NMR (300 MHz) (CDCl₃): δ TMS 3.50 (2H, d, J ) 1.0 Hz),

3.87 (3H, s), 5.49 (1H, s, D₂O exch), 6.60 (1H, d, J ) 8.1 Hz), 6.86

(1H, d, J ) 8.0 Hz), 7.94 (1H, s, D₂O exch). IR (KBr): 3287, 3014,

2953, 1686, 1633, 1504, 1466, 1315, 1163, 637 cm^-1. Microanal. Calcd

for C₉H₉NO₃: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.51; H, 5.05;

N, 7.60.

Compound 26 was also obtained from 28 as follows: To a solution

of 28 (76.2 mg, 0.39 mmol, 1.0 equiv) in HMPA (2 mL) under N₂at

room temperature was added MTPI (291.5 mg, 0.64 mmol, 1.6 equiv)

all at once. After being stirred for 1 day, the mixture was poured into

a separatory funnel containing 1 M NaOH and was extracted with ether.

The organic layer was washed with brine and dried over MgSO₄.

Evaporation gave a crude yield of 163.5 mg. The crude product was

purified by radial chromatography (eluted with 1:10 EtOAc/hexanes,

then 1:5 EtOAc/hexanes) to afford 46 mg (66%) of 26.

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.42 (6H, s), 4.81 (1H, d, J

) 7.8 Hz), 6.30 (1H, d, J ) 7.8 Hz), 6.95-7.06 (4 H, m). IR (neat):

2978, 1654, 1587, 1495, 1311, 1242, 750 cm^-1

176.0835 (C₁₁H₁₂O₂requires 176.0837).

.

HRMS (EI): m/e

(()-2-[(3,3-Dimethyloxiranyl)methoxy]phenol (27). To a solution

of 24 (1.31 g, 7.35 mmol, 1.0 equiv) in CH₂Cl₂(40.0 mL) under N₂at

0 °C was added NaHCO₃(803 mg, 9.56 mmol, 1.3 equiv) followed by

m-CPBA (1.27 g, 7.35 mmol, 1.0 equiv). After 1.5 h additional

NaHCO₃(812 mg, 9.66 mmol, 1.21 equiv) and m-CPBA (1.26 g, 7.35

mmol, 0.99 equiv) were added. This mixture was kept stirring at 0 °C

for 2 h, when more NaHCO₃(778 mg, 9.27 mmol, 1.3 equiv) and

m-CPBA (1.12 g, 6.49 mmol, 0.88 mmol) were added. After 2 h, the

cold mixture was filtered to remove the solids. The filtrate was washed

three times with 10% Na₂S₂O₃and three times with brine, dried over

MgSO₄, and evaporated to dryness to afford 1.41 g (99%) of 27. An

analytical sample was recrystallized from toluene to give a glassy solid,

mp 36-37 °C.

1,3-Dihydro-7-methoxy-6-[(tolylsulfonyl)oxy]-2H-indol-2-one. To

a stirred mixture of 31 (321.6 mg, 1.795 mmol, 1.0 equiv) in acetone

(7 mL) at 0 °C under Ar were added K₂CO₃(740.5 mg, 5.358 mmol,

2.98 equiv) and p-toluenesulfonyl chloride (376.4 mg, 1.974 mmol,

1.1 equiv). The mixture was stirred for 5 h at 0 °C and 1 h at room

temperature. The reaction mixture was diluted with water and extracted

with EtOAc. The organic layer was washed three times with 1 M

NaOH and once with brine, dried over MgSO₄, and concentrated to

dryness. The product, 572.3 mg (96%), was obtained as a rust-colored,

amorphous solid.

¹H NMR (270 MHz) (CDCl₃): δ 2.47 (3H, s), 3.52 (2H, s), 3.81

(3H, s), 6.70 (1H, d, J ) 8.2 Hz), 6.86 (1H, d, J ) 8.1 Hz), 7.34 (2H,

d, J ) 8.1 Hz), 7.79 (2H, d, J ) 8.3 Hz), 7.85 (1H, s, D₂O exch). IR

(KBr): 3172 (br), 1709, 1616, 1496, 1458, 1371, 1338, 1175, 1093,

1050, 1000, 848, 815, 728, 662, 548, cm^-1. Mass spectrum (EI): m/e

(relative intensity) 333 (5.0), 269 (1.4), 178 (40), 91 (77), 28 (100).

¹H NMR (270 MHz) (CDCl₃): δ TMS 1.37 (3H, s), 1.41 (3H, s),

3.18 (1H, dd, J ) 4.2, 6.3 Hz), 4.07 (1H, dd, J ) 6.4, 11.0 Hz), 4.28

(1H, dd, J ) 4.2, 11.0 Hz), 5.78 (1H, s, D₂O exch), 6.81-6.97 (4H,

m). IR (NaCl, neat): 3413, 2966, 1590, 1502, 1267, 744 cm^-1

.

Microanal. Calcd for C₁₁H₁₄O₄: C, 68.02; H, 7.26. Found: C, 67.91;

H, 7.39.

(()-3,4-Dihydro-2,2-dimethyl-2H-1,5-benzodioxepin-3-ol (28). A

flame-dried flask, flushed with Ar, was charged with dry THF (85.4

mL). Tin tetrachloride (0.85 mL, 7.3 mmol, 1.0 equiv) was then added

dropwise in 5 min. After 10 min a solution of 27 (1.41 g, 7.26 mmol,

1.0 equiv) in dry THF (13.8 mL) was added slowly (dropwise) to the

mixture. The reaction mixture was stirred at room temperature for 20

min, poured into saturated NaHCO₃, washed with brine, dried over

1,3-Dihydro-7-hydroxy-6-[(tolylsulfonyl)oxy]-2H-indol-2-one. Bo-

ron tribromide (1.1 mL, 1.1 mmol, 2.0 equiv, 1 M/CH₂Cl₂) was added

to a stirred mixture of 1,3-dihydro-7-methoxy-6-[(tolylsulfonyl)oxy]-

2H-indol-2-one obtained above (181.5 mg, 0.54 mmol, 1.0 equiv) in

CH₂Cl₂(4.3 mL) under Ar, at -78 °C. The mixture was stirred for 8

h and stored at -20 °C for 12 h. The mixture was poured into ice/

570 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

water, stirred for 0.5 h, and extracted with EtOAc. The organic layer

was washed with brine, dried over MgSO₄, and concentrated to dryness

to give 164.7 mg (95%) of a red solid.

Na₂S₂O₃and 10% NaHCO₃. The organic layer was isolated, diluted

with CH₂Cl₂, and washed with 10% Na₂S₂O₃and saturated NaHCO₃

and finally with brine. The organic layer was dried over Na₂SO₄,

filtered, concentrated under reduced pressure, and dried in vacuo to

yield 17 g of the product, which was used directly for the next step.

An analytical sample was recrystallized from toluene to give a white

solid, mp 122-123 °C.

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.38 (3H, s), 1.42 (3H, s),

3.25 (1H, dd, J ) 2.9, 8.5 Hz), 3.47-3.49 (2H, m), 3.80 (1H, dd, J )

8.5, 12.0 Hz), 4.54 (1H, dd, J ) 2.9, 12.0 Hz), 6.25 (1H, s, D₂O exch),

6.58 (1H, d, J ) 8.1 Hz), 6.84 (1H, d, J ) 8.1 Hz), 8.44 (1H, s, D₂O

exch). IR (KBr): 3495, 3146, 2982, 1717, 1694, 1635, 1501, 1466,

1321, 1187, 1047, 861 cm^-1. Microanal. Calcd for C₁₃H₁₅NO₄: C,

62.64; H, 6.06; N, 5.62. Found: C, 62.70; H, 6.15; N, 5.66.

¹H NMR (270 MHz) (acetone-d₆): δ TMS 2.45 (3H, s), 3.43 (2H,

d, J ) 0.8 Hz), 6.61 (1H, d, J ) 8.1 Hz), 6.71 (1H, d, J ) 8.1 Hz),

7.46 (2H, d, J ) 8.6 Hz), 7.79 (2H, d, J ) 8.3 Hz), 8.50 (1H, s, D₂O

exch), 9.28 (1H, s, D₂O exch). IR (NaCl, neat): 3259 (br), 2921, 1698,

1365, 1175, 1142, 728 cm^-1

. Mass spectrum (EI): m/e (relative

intensity) 319 (3.4), 278 (6.0), 246 (6.7), 163 (49), 139 (73), 91 (100).

1,3-Dihydro-7-[(3-methyl-2-butenyl)oxy]-6-[(tolylsulfonyl)oxy]-

2H-indol-2-one (37). To a stirred solution of 1,3-dihydro-7-hydroxy-

6-[(tolylsulfonyl)oxy]-2H-indol-2-one obtained above (159.4 mg, 0.49

mmol, 1.0 equiv) in DMF (1.5 mL) at 0 °C was added K₂CO₃(103.5

mg, 0.75 mmol, 1.5 equiv) followed by prenyl bromide (0.09 mL, 0.75

mmol, 1.5 equiv). After 4 h the mixture was poured into water,

extracted with EtOAc, washed with brine, dried over MgSO₄, and

concentrated to dryness. The product was purified by radial chroma-

tography (eluted with 3:2 hexanes/EtOAc) to afford 71.9 mg (37%) of

37 as a red solid.

¹H NMR (270 MHz) (CDCl₃): δ TMS 1.58 (3H, s), 1.70 (3H, s),

2.45 (3H, s), 3.52 (2H, s), 4.47 (2H, d, J ) 7.3 Hz), 5.35 (1H, t, J )

7.3 Hz), 6.74 (1H, d, J ) 8.2 Hz), 6.87 (1H, d, J ) 8.1 Hz), 7.32 (2H,

d, J ) 8.0 Hz), 7.79 (2H, d, J ) 8.3 Hz), 8.61 (1H, s, D₂O exch). IR

(NaCl, neat): 3194 (br), 1714, 1627, 1464, 1376, 1196, 1175, 837,

728 cm^-1. Mass spectrum (EI): m/e (relative intensity) 387 (16), 319

(16), 164 (37), 91 (91), 67 (100).

1,3-Dihydro-6,7-dihydroxy-2H-indol-2-one (32). Boron tribromide

(800 mL, 800 mmol, 2.5 equiv, 1M/CH₂Cl₂) was added dropwise to a

stirred mixture of 31 (57.3 g, 320 mmol, 1.0 equiv)) in CH₂Cl₂(640

mL) under N₂at -78 °C. The reaction mixture was stirred at -78 °C

for 8 h and was then poured into a large (4 L) beaker containing 1.5 L

of ice/water, stirred for 10 min, and filtered to remove undissolved

product. The remaining liquid was extracted with EtOAc, washed with

brine, and dried over MgSO₄. The organic layer was evaporated to

yield the pure product 32, which was combined with the filter cake,

total yield 52.3 g (99%). An analytical sample was recrystallized from

H₂O (three times) to give a faint pink crystalline solid, mp 245 °C

dec.

(()-3,4,8,10-Tetrahydro-3-hydroxy-4,4-dimethyl-2H,9H-[1,4]di-

oxepino[2,3-g]indol-9-one (34). SnCl₄(9.6 mL, 81.8 mmol, 1.2 equiv)

was slowly added dropwise to a flame-dried flask, which had been

flushed with Ar and charged with dry THF (960 mL). After 10 min a

solution of (()-1,3-dihydro-7-[(3,3-dimethyloxiranyl)methoxy]-6-hy-

droxy-2H-indol-2-one obtained above (17 g, 62 mmol, 1.0 equiv) in

THF (73 mL) was added dropwise to the reaction vessel and stirred

for 2 h. Approximately one-half of the solvent was removed under

reduced pressure and the remaining solution poured into a separatory

funnel containing saturated NaHCO₃and H₂O (∼50:50), which was

then exhaustively extracted with CH₂Cl₂. The organic layer was washed

with brine, dried over Na₂SO₄, and evaporated to give a dark crude

product. The product was purified by column chromatography (eluted

with 1:2 hexanes/EtOAc) to yield 10 g (64% for two steps) of 34. An

analytical sample was recrystallized from toluene to give a yellow

crystalline solid, mp 194 °C.

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.24 (3H, s), 1.54 (3H, s),

2.94 (1H, d, J ) 11.2 Hz, D₂O exch), 3.51 (2H, s), 3.63 (1H, ddd, J )

1.0, 4.0, 11.2 Hz), 4.12 (1H, dd, J ) 1.0, 12.4 Hz), 4.24 (1H, dd, J )

4.0, 12.5 Hz), 6.64 (1H, d, J ) 8.0 Hz), 6.83 (1H, d, J ) 7.9 Hz), 7.64

(1H, s, D₂O exch). IR (KBr): 3460, 3320, 3169, 2982, 1711, 1682,

1461, 1327, 1216, 1047 cm^-1. Microanal. Calcd for C₁₃H₁₅NO₄: C,

62.64; H, 6.08; N, 5.61. Found: C, 62.28; H, 6.21; N, 5.56.

(()-3-Hydroxy-4,4-dimethyl-3,4,dihydro-2H,10H-[1,4]dioxepino-

[2,3-g]indole (35). To a stirred solution of 34 (11.2 g, 44.8 mmol, 1.0

equiv) in THF (225 mL) under Ar at 0 °C was added BF₃‚OEt₂(19.3

mL, 157 mmol, 3.5 equiv). After 10 min, NaBH₄(2.71 g, 71.8 mmol,

1.6 equiv) was added at once, and the mixture was stirred for 8 h at 0

°C and then at room temperature for 40 h. The reaction was completed

by the slow addition of water (1 L) and was stirred for 0.5 h. HCl

(concentrated) was added until pH ) 1, and the mixture was stirred

for an additional 0.5 h. The mixture was treated with 1 M NaOH until

pH ) 14 and stirred for 0.5 h. The mixture was poured into a separatory

funnel and extracted with EtOAc/ether. The organic layer was washed

with brine, dried over Na₂SO₄, and evaporated to leave 10 g of a crude

solid. The product was purified by column chromatography (eluted

with 2:1 hexanes/EtOAc) to yield 4.5 g (43%) of 35. An analytical

sample was recrystallized from benzene to afford a white crystalline

solid, mp 202-205 °C.

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.22 (3H, s), 1.56 (3H, s),

3.03 (1H, d, J ) 11.4 Hz, D₂O exch), 3.63 (1H, ddd, J ) 4.0, 0.9, 11.3

Hz), 4.19 (1H, dd, J ) 0.9, 12.3 Hz), 4.31 (1H, dd, J ) 4.0, 12.3 Hz),

6.49 (1H, dd, J ) 2.2, 3.1 Hz), 6.78 (1H, d, J ) 8.4 Hz), 7.16-7.19

(2H, m), 8.29 (1H, s, D₂O exch). IR (KBr): 3340, 2984, 1580, 1504,

1444, 1338, 1224, 1133, 1057, 814, 753 cm^-1. Microanal. Calcd for

C₁₃H₁₅NO₃: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.16; H, 6.63; N,

5.79.

¹H NMR (300 MHz) (DMSO-d₆): δ TMS 3.32 (2H, s), 6.36 (1H,

d, J ) 7.9 Hz), 6.48 (1H, d, J ) 2.9 Hz), 8.80 (2H, br s, D₂O exch),

10.0 (1H, br s, D₂O exch). IR (KBr): 3366-3123 (br), 1672, 1649,

1618, 1359, 1265, 1178, 786 cm^-1. Microanal. Calcd for C₈H₇NO₃:

C, 58.18; N, 4.27; N, 8.48. Found: C, 58.34; H, 4.44; N, 8.25.

1,3-Dihydro-6-hydroxy-7-[(3-methyl-2-butenyl)oxy]-2H-indol-2-

one (33). To a stirred solution of 6,7-dihydroxyoxindole (32) (19.0 g,

115 mmol, 1.0 equiv) in DMF (230 mL) at 0 °C under Ar was added

K₂CO₃(15.9 g, 115 mmol, 1.0 equiv). After 8 min prenyl bromide

(14.8 mL, 127 mmol, 1.1 equiv) was added dropwise. The reaction

mixture was stirred at 0 °C for 6.5 h, poured into a separatory funnel,

diluted with H₂O, and extracted with ether. The ethereal solution was

washed with brine, dried over Na₂SO₄, and evaporated to dryness. The

product was purified by column chromatography (eluted with 3:1

hexanes/EtOAc, then 1:1 hexanes/EtOAc) to yield 14.5 g (54%) of

33. An analytical sample was recrystallized from toluene to give a

red-white solid, mp 111 °C.

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.65 (3H, s), 1.80 (3H, s),

3.50 (2H, s), 4.47 (1H, d, J ) 7.4 Hz), 5.50-5.55 (1H, m), 5.57 (1H,

s, D₂O exch), 6.59 (1H, d, J ) 8.1 Hz), 6.84 (1H, d, J ) 8.0 Hz), 7.77

(1H, s, D₂O exch). IR (KBr): 3367, 3192, 2971, 1694, 1664, 1635,

1461, 1356, 1286, 1199, 1047 cm^-1. Microanal. Calcd for C₁₃H₁₅-

NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.16; H, 6.52; N, 6.07.

(()-1,3-Dihydro-7-[(3,3-dimethyloxiranyl)methoxy]-6-hydroxy-

2H-indol-2-one. To a stirred solution of 33 (14.5 g, 62.1 mmol, 1.0

equiv) in CH₂Cl₂(620 mL) were added NaHCO₃(5.7 g, 68.3 mmol,

1.1 equiv) and m-CPBA (10.7 g, 62.1 mmol, 1.0 equiv). The mixture

was stirred for 1 h, and an additional amount of each reagent was added,

NaHCO₃(5.7 g, 68.3 mmol, 1.1 equiv) and m-CPBA (10.7 g, 62.1

mmol, 1.0 equiv). The mixture was stirred for an additional 1 h, and

a third portion each of NaHCO₃(5.7 g, 68.3 mmol, 1.1 equiv) and

m-CPBA (10.7 g, 62.1 mmol, 1.0 equiv) was added. The resulting

mixture was stirred for 3 h, while the temperature was maintained at

0 °C. The reaction mixture was filtered into a flask containing 10%

(()-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-3,4-di-

hydro-2H,10H-[1,4]dioxepino[2,3-g]indole. To a stirred solution of

35 (11.6 g, 49.7 mmol, 1.0 equiv) in DMF (124 mL) at room

temperature under N₂was added tert-butyldimethylsilyl chloride (15.0

g, 99.4 mmol, 2.0 equiv) immediately followed by imidazole (23.7 g,

348 mmol, 7.0 equiv). The solution was slowly heated to 40 °C, stirred

overnight, poured into a separatory funnel, and extracted with EtOAc.

The organic layer was washed with brine and dried over Na₂SO₄. The

solvent was removed and the crude solid purified by column chroma-

tography (eluted with 5:1 hexanes/EtOAc) to yield 14.2 g (82%) of

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 571

the product. An analytical sample was recrystallized from cyclohexane

to give a white solid, mp 118-119 °C.

was diluted with 1:1 EtOAc/hexanes and washed with water (5×) and

brine. The organic layer was dried over MgSO₄and concentrated to

dryness. The product was purified by PTLC on silica gel (eluted with

1:3 EtOAc/hexanes) to yield 8.9 mg (39%) of 40 (oil) and 2.7 mg (12%)

of 41 (oil). Total yield: 51%.

¹H NMR (300 Hz) (CDCl₃): δ TMS 0.14 (6H, s), 0.89 (9H, s),

1.12 (3H, s), 1.48 (3H, s), 3.88 (1H, dd, J ) 9.2, 11.5 Hz), 3.98 (1H,

dd, J ) 3.2, 9.2 Hz), 4,22 (1H, dd, J ) 3.2, 11.5 Hz), 6.48 (1H, dd, J

) 2.2, 3.1 Hz), 6.76 (1H, d, J ) 8.4 Hz), 7.14 (2H, ddd, J ) 2.4, 3.4,

3.5 Hz), 8.21 (1H, s, D₂O exch). IR (neat): 3412, 2936, 1500, 1438,

1234, 1093, 833 cm^-1. Microanal. Calcd for C₁₉H₂₉NO₃Si: C, 65.66;

H, 8.41; N, 4.03. Found: C, 65.59; H, 8.20; N, 3.90.

¹H NMR (300 MHz) (CDCl₃) (a racemic mixture of two diastere-

omers) (40): δ 0.036 (12H, s), 0.12 (6H, s), 0.13 (6H, s), 0.84 (9H, s),

0.87 (9H, s), 0.88 (9H, s), 0.882 (9H, s), 1.10 (3H, s), 1.11 (3H, s),

1.458 (9H, s), 1.463 (3H, s), 1.72-2.04 (10H, m), 2.12-2.23 (2H, m),

3.24-3.51 (8H, m), 3.72 (3H, s), 3.73 (3H, s), 3.79-3.82 (6H, m),

3.83 (2H, s), 3.86 (2H, s), 4.15-4.20 (4H, m), 5.15 (1H, ¹/₂ABq, J )

(()-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-8-[(N,N-

dimethylamino)methyl]-3,4-dihydro-2H,10H-[1,4]dioxepino[2,3-g]-

indole (36). To a flask charged with acetic acid (136 mL) under Ar

were added formaldehyde (3.4 mL, 45 mmol, 1.1 equiv, 37%/H₂O)

and dimethylamine (20.5 mL, 163 mmol, 4.0 equiv, 40% solution in

H₂O) followed by (()-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-

dimethyl-3,4,dihydro-2H,10H-[1,4]dioxepino[2,3-g]indole obtained above

(14.2 g, 40.9 mmol, 1.0 equiv) over a 10 min period. The reaction

mixture was stirred for 1 day when 10% K₂CO₃was added until pH ≈

8; then 2 M NaOH was added. The mixture was extracted with ether/

EtOAc, washed with brine, and dried over Na₂SO₄. The solvent was

removed under reduced pressure, leaving 17.3 g (quantitative) of the

pure product 36. An analytical sample was recrystallized from toluene

to give a white flaky solid, mp 152 °C.

¹H NMR (300 Hz) (CDCl₃): δ TMS 0.15 (6H, s), 0.90 (9H, s),

1.13 (3H, s), 1.48 (3H, s), 2.28 (6H, s), 3.58 (2H, s), 3.58 (2H, s), 3.88

(1H, dd, J ) 9.2, 11.4 Hz), 3.98 (1H, dd, J ) 3.2, 9.1 Hz), 4.21 (1H,

dd, J ) 3.2, 11.5 Hz), 6.76 (1H, d, J ) 8.4 Hz), 8.44 (1H, s, D₂O

exch). IR (NaCl, neat): 2932, 1502, 1458, 1360, 1251, 1218, 1093,

837, 777 cm^-1. Microanal. Calcd for C₂₂H₃₆N₂O₃Si: C, 65.31; H,

8.97; N, 6.92. Found: C, 65.09; H, 8.77; N, 6.73.

(()-6(R)-(2E)-Methyl 3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]-

oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indol-

8-yl]methyl]-8a-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-methyl-

2-butenyl]-2-[(4-methoxyphenyl)methyl]octahydro-1,4-

dioxopyrrolo[1,2-a]pyrazine-3-carboxylate (39). To a stirred solution

of 38 (23.0 mg, 0.043 mmol, 1.0 equiv) in CH₃CN (0.3 mL) and PBu₃

(5.4 µL, 0.022 mmol, 0.5 equiv) was added a solution of 36 (19.3 mg,

0.048 mmol, 1.1 equiv) in CH₃CN (0.3 mL). The mixture was refluxed

for 5.5 h and stirred at room temperature overnight. The reaction

mixture was then diluted with ether, washed with water, dilute HCl,

and brine, and dried over MgSO₄. The solvent was removed and the

crude oily solid purified by PTLC on silica gel (eluted with 1:4 EtOAc/

hexanes) to yield 19.8 mg (51%) of 39. An analytical sample was

recrystallized from cyclohexane to give a white crystalline solid, mp

168-168.5 °C.

1

14.2 Hz), 5.20 (1H, /₂ABq, J ) 14.2 Hz), 5.28 (1H, m), 5.45 (1H,

m), 6.67-6.71 (4H, m), 6.76 (2H, d, J ) 8.5 Hz), 6.81-6.90 (6H, m),

7.16 (2H, d, J ) 8.5 Hz), 8.12 (2H, s, D₂O exch). IR (syn) (NaCl,

neat): 2920, 1655, 1508, 1449, 1250, 1220, 1091, 838 cm^-1

.

¹H NMR (300 MHz) (CDCl₃) (a racemic mixture of two diastere-

omers) (41): δ -0.18 (12H, s), 0.12 (6H, s), 0.13 (6H, s), 0.26-0.41

(2H, m), 0.47-0.58 (2H, m), 0.62-0.72 (2H, m), 0.84 (18H, s), 0.87

(9H, s), 0.89 (9H, s), 1.06 (3H, s), 1.10 (3H, s), 1.44 (6H, s), 1.47 (3H,

s), 1.48 (3H, s), 1.63-1.67 (2H, m), 2.10-2.17 (2H, m), 2.44-2.52

(2H, m), 2.89-3.05 (2H, m), 3.20-3.28 (2H, m), 3.40-3.52 (4H, m),

3.71-3.97 (16H, m), 4.08 (2H, br s), 4.14-4.21 (2H, m), 5.05 (2H, br

s), 5.56 (1H, ¹/₂ABq, J ) 14.2 Hz), 5.57 (1H, ¹/₂ABq, J ) 14.5 Hz),

6.71 (1H, d, J ) 8.6 Hz), 6.73 (1H, d, J ) 8.6 Hz), 6.83-6.88 (6H,

m), 7.14 (1H, d, J ) 8.6 Hz), 7.18 (1H, d, J ) 8.6 Hz), 7.22-7.23

(4H, m), 8.34 (2H, s, D₂O exch). IR (anti) (neat): 2932, 1649, 1508,

1455, 1250, 1220, 1103, 838 cm^-1. HRMS (EI) (anti): 831.46765

(C₄₆H₆₉N₃O₇Si₂requires 831.4674).

[(()-[3r,8ar(E)]]-1,1-Dimethylethyl 8-[[3-(Methoxycarbonyl)-2-

[(4-methoxyphenyl)methyl]-8a-[4-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-3-methyl-2-butenyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-

4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate (42).

To a stirred solution of 39 (260.0 mg, 0.292 mmol, 1.0 equiv) in CH₂-

Cl₂(1.5 mL) at 0 °C under Ar were added DMAP (35.7 mg, 0.292

mmol, 1.0 equiv) and Et₃N (0.041 mL, 0.29 mmol, 1.0 equiv). After

5 min (BOC)₂O (191.2 mg, 0.876 mmol, 3.0 equiv) was added in one

portion. The resulting solution was stirred for 20 h, poured into water,

and extracted with EtOAc. The organic layer was washed with brine,

dried over Na₂SO₄, and concentrated under reduced pressure. The crude

solid was purified by radial chromatography (eluted with 1:5 EtOAc/

hexanes) to yield 260.4 mg (90%) of 42 as a white crystalline solid,

mp 74-75 °C.

¹H NMR (300 MHz) (CDCl₃): δ -0.01 (6H, s), 0.00 (6H, s), 0.113

(6H, s), 0.12 (6H, s), 0.58-0.68 (2H, m), 0.80-0.92 (38H, m), 1.06

(6H, s), 1.45-1.63 (2H, m), 1.47 (6H, s), 1.53 (6H, s), 1.60 (18H, s),

1.59-1.81 (2H, m), 2.22-2.34 (2H, m), 2.60 (2H, dd, J ) 8.1, 15.0

Hz), 2.91-3.08 (2H, m), 3.26 (6H, s), 3.26-3.42 (2H, m), 3.56 (1H,

¹H NMR (300 MHz) (CDCl₃) (a racemic mixture of two diastere-

omers): δ TMS 0.00 (6H, s), 0.01 (6H, s), 0.13 (6H, s), 0.14 (6H, s),

0.034-0.19 (2H, m), 0.43-0.52 (2H, m), 0.62-0.72 (2H, m), 0.84

(9H, s), 0.85 (9H, s), 0.86 (9H, s), 0.88 (9H, s), 1.05 (3H, s), 1.1 (3H,

s), 1.45 (3H, s), 1.49 (3H, s), 1.537 (3H, s), 1.544 (3H, s), 1.33-1.67

(2H, m), 2.14-2.25 (2H, m), 2.52-2.60 (2H, m), 2.87-3.03 (2H, m),

1

¹/₂ABq, J ) 14.8 Hz), 3.59 (1H, /₂ABq, J ) 14.8 Hz), 3.71-3.80

(4H, m), 3.74 (6H, s), 3.83 (2H, s), 3.84 (2H, s), 3.90-3.97 (4H, m),

1

4.13-4.17 (2H, m), 3.32 (2H, m), 5.34 (1H, /₂ABq, J ) 14.8 Hz),

3.27 (6H, s), 3.36-3.52 (2H, m), 3.66 (1H, /₂ABq, J ) 15.0 Hz),

5.42 (1H, ¹/₂ABq, J ) 14.8 Hz), 6.75-6.79 (4H, m), 6.88 (1H, d, J )

8.4 Hz), 6.89 (1H, d, J ) 8.4 Hz), 7.03 (2H, s), 7.12-7.20 (6H, m).

IR (NaCl, neat): 2943, 1752, 1660, 1507, 1496, 1464, 1463, 1404,

1365, 1251, 1153, 1109, 1082, 837, 772 cm^-1. HRMS (EI): 989.5249

(C₅₃H₇₉N₃O₁₁Si₂requires 989.5253).

1

3.66 (1H, /₂ABq, J ) 15.0 Hz), 3.75 (6H, s), 3.77-3.96 (12H, m),

1

4.14-4.20 (2H, m), 5.25-5.31 (2H, m); 5.48 (2H, /₂ABq, J ) 14.6

Hz), 6.70-6.89 (8H, m), 7.15-7.22 (6H, m), 8.29 (1H, s, D₂O exch),

8.32 (1H, s, D₂O exch). IR (NaCl, neat): 3303, 2954, 2856, 1752,

1660, 1512, 1447, 1251, 1098, 1049, 837, 777 cm^-1. Microanal. Calcd

for C₄₈H₇₁N₃O₉Si₂: C, 64.76; H, 8.04; N, 4.72. Found: C, 64.95; H,

8.09; N, 4.53.

[(()-[3â,8aâ(E)]]-1,1-Dimethylethyl 8-[[8a-[4-[[(1,1-Dimethyleth-

yl)dimethylsilyl]oxy]-3-methyl-2-butenyl]-2-[(4-methoxyphenyl)-

methyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-

[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-

2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate (syn-43). [(()-

[3r,8aâ(E)]]-1,1-Dimethylethyl 8-[[8a-[4-[[(1,1-Dimethylethyl)di-

methylsilyl]oxy]-3-methyl-2-butenyl]-2-[(4-methoxyphenyl)methyl]-

octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-dim-

ethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]-

dioxepino[2,3-g]indole-10-carboxylate (anti-43). A flask containing

42 (126.6 mg, 0.128 mmol, 1.0 equiv) and LiCl (27.1 mg, 0.64 mmol,

5.0 equiv) under N₂was charged with HMPA (0.78 mL) and H₂O (3.4

× 10^-3mL, 1.9 × 10^-4mmol, 1.5 equiv). The solution was heated

(100-105 °C) for 1.25 h and then poured into water and extracted

with ether. The organic layer was washed with water and brine, dried

over MgSO₄, and concentrated, leaving a crude oily solid. The product

[(()-[3r,8aâ(E)]]-8-[[2-[(4-Methoxyphenyl)methyl]-8a-[4-[[(1,1-

dimethylethyl)dimethylsilyl]oxy]-3-methyl-2-butenyl]octahydro-1,4-

dioxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-dimethylethyl)-

dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-

[1,4]dioxepino[2,3-g]indole (40). [(()-[3â,8ar(E)]]-8-[[2-[(4-Meth-

oxyphenyl)methyl]-8a-[4-[[(1,1-dimethylethyl) dimethylsilyl]oxy]-

3-methyl-2-butenyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-3-yl]-

methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-

dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole (41). A dry flask

containing 39 (24.4 mg, 0.027 mmol, 1.0 equiv) and lithium chloride

(11.6 mg, 0.27 mmol, 10 equiv) under N₂was charged with HMPA

(0.21 mL) and water (1.5 × 10^-3mL, 0.082 mmol, 3.0 equiv). This

mixture was heated to 100-105 °C for 2 h. The resulting solution

572 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

was purified by radial chromatography (eluted with 1:5 EtOAc/hexanes)

to yield 79.2 mg (66%) of syn-43 (an analytical sample was obtained

by PTLC, eluted with 1:5 EtOAc/hexanes, to give an oil) and 3.1 mg

(2.6%) of the anti-isomer (oil).

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.22 (3H, s), 1.23 (3H, s),

1.57 (3H, s), 1.58 (3H, s), 1.62 (9H, s), 1.63 (9H, s), 1.66 (3H, s), 1.73

(3H, s), 1.83-1.93 (8H, m), 2.05-2.37 (4H, m), 3.06 (2H, dd, J )

3.8, 11.4 Hz), 3.35-3.42 (6H, m, 1H, D₂O exch), 3.46-3.69 (4H, m),

3.75 (3H, s), 3.77 (3H, s), 3.86-3.94 (2H, m), 3.96 (2H, s), 4.02 (2H,

s), 4.21-4.29 (6H, m), 5.20-5.29 (3H, m), 5.53 (1H, m), 6.69-6.81

(6H, m), 6.94-6.99 (4H, m), 7.18-7.21 (4H, m). IR (NaCl, neat):

¹H NMR (300 MHz) (CDCl₃) (syn-43): δ 0.026 (6H, s), 0.32 (6H,

s), 0.127 (6H, s), 0.14 (6H, s), 0.867 (9H, s), 0.873 (9H, s), 0.878 (9H,

s), 0.883 (9H, s), 1.10 (6H, s), 1.48 (3H, s), 1.49 (3H, s), 1.55 (3H, s),

1.57 (3H, s), 1.610 (9H, s), 1.613 (9H, s), 1.83-1.96 (6H, s), 2.22-

2.35 (4H, m), 2.46 (2H, dd, J ) 6.0, 15.0 Hz), 3.11-3.21 (2H, m),

3433, 2976, 1752, 1654, 1513, 1496, 1453, 1371, 1251, 1153 cm^-1

.

1,1-Dimethylethyl 8-[[8a-[4-Hydroxy-3-methyl-2-butenyl]-2-[(4-

methoxyphenyl)methyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-

4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate (46).

To a solution of 45 (28.2 mg, 0.04 mmol, 1.0 equiv) in CH₂Cl₂(0.3

mL) at 0 °C under Ar was added tert-butyldimethylsilyl triflate (9.0

µL, 0.04 mmol, 1.2 equiv) followed immediately by 2,6-lutidine (6.0

µL, 0.047 mmol, 1.4 equiv). The mixture was stirred for 2 h, then

diluted with EtOAc, washed with water and brine, dried over MgSO₄,

and concentrated under reduced pressure. The product was purified

by radial chromatography (eluted with 1:1 EtOAc/hexanes) to yield

24.9 mg (76%) of 46 as an oil.

1

3.31-3.85 (2H, m), 3.37 (1H, /2ABq, J ) 14.5 Hz), 3.48 (1H, /₂

ABq, J ) 14.6 Hz), 3.71 (3H, s), 3.72 (3H, s), 3.76-3.98 (8H, m),

1

3.99 (2H, m), 4.02 (2H, s), 4.15-4.21 (4H, m), 5.17 (1H, /₂ABq, J

) 14.5 Hz), 5.20 (1H, ¹/₂ABq, J ) 14.6 Hz), 5.35 (1H, m), 5.48 (1H,

m), 6.62-6.70 (6H, m), 6.79 (2H, m), 6.91 (2H, d, J ) 8.3 Hz), 7.14

(1H, d, J ) 8.4 Hz), 7.16 (1H, d, J ) 8.3 Hz), 7.22 (1H, s), 7.23 (1H,

s). IR (NaCl, neat) (syn): 2932, 1755, 1661, 1455, 1367, 1250, 1156,

1114,1091, 838 cm^-1. HRMS (EI) (syn): 931.51955 (C₅₁H₇₇N₃O₉Si₂

requires 931.5198). Microanal. Calcd for C₅₁H₇₇N₃O₉Si₂: C, 65.70;

H, 8.32; N, 4.51. Found: C, 65.37; H, 8.37; N, 4.54.

¹H NMR (300 MHz) (CDCl₃) (anti): δ -0.02 (6H, s), -0.01 (6H,

s), 0.03-0.22 (2H, m), 0.12 (6H, s), 0.13 (6H, s), 0.146-0.62 (4H,

m), 0.84 (9H, s), 0.85 (9H, s), 0.87 (18H, s), 1.05 (3H, s), 1.07 (3H,

s), 1.43 (3H, s), 1.47 (3H, s), 1.49 (3H, s), 1.52 (3H, s), 1.55 (9H, s),

1.60 (9H, s), 1.80-1.91 (2H, m), 2.19-2.22 (2H, m), 2.50-2.61 (2H,

m), 3.09-3.23 (2H, m), 3.29-3.52 (4H, m), 3.63-3.96 (18H, m),

4.13-4.20 (4H, m), 5.04-5.10 (1H, m), 5.28-5.32 (1H, m), 5.48 (1H,

¹H NMR (300 MHz) (CDCl₃): δ 0.12 (6H, s), 0.13 (6H, s), 0.87

(9H, s), 0.88 (9H, s), 1.08 (3H, s), 1.10 (3H, s), 1.48 (6H, s), 1.61 (9H,

s), 1.63 (9H, s), 1.69 (3H, s), 1.79 (3H, s), 1.82-2.03 (8H, m), 2.16-

2.24 (4H, m), 3.19 (2H, dd, J ) 7.2, 8.5 Hz), 3.25-3.39 (4H, m), 3.49

1

(1H, /₂ABq, J ) 14.5 Hz), 3.65 (1H, /₂ABq, J ) 14.5 Hz), 3.72

(3H, s), 3.76 (3H, s), 3.79-3.99 (8H, m), 4.15-4.22 (4H, m), 5.19-

5.28 (4H, m), 5.49 (2H, m), 6.67-6.81 (6H, m), 6.92 (4H, dd, J )

1.9, 8.4 Hz), 7.13 (1H, d, J ) 8.4 Hz), 7.14 (1H, d, J ) 8.4 Hz), 7.20

(1H, s), 7.24 (1H, s). IR (NaCl, neat): 2932, 1752, 1654, 1512, 1491,

1

¹/₂ABq, J ) 14.3 Hz), 5.52 (1H, /₂ABq, J ) 14.3 Hz), 6.71-6.90

(6H, m), 7.04-7.22 (8H, m). IR (NaCl, neat) (anti: 3295 (br), 1753,

1447, 1365, 1251, 1153, 1088, 837 cm^-1

.

1657, 1510, 1447, 1249, 1152, 1090, 1034, 836, 773 cm^-1

.

[(()-[3r,8ar,10(R*)]]-1,1-Dimethylethyl 8-[[Tetrahydro-2-[(4-

methoxyphenyl)methyl]-10-(1-methylethenyl)-1,4-dioxo-6H-3,8a-

ethanopyrrolo[1,2-a]pyrazin-3(4H)-yl]methyl]-3-[[(1,1-dimethylethyl)-

dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-

[1,4]dioxepino[2,3-g]indole-10-carboxylate (47). To 46 (24.0 mg,

0.028 mmol, 1.0 equiv) in a flask equipped with a magnetic stir bar

were added NaH (12.3 mg, 0.3 mmol, 10.8 equiv) and benzene (3.5

mL). The flask was fitted with a condenser and gently refluxed for 59

h (additional benzene (1.5 mL) was added during this time). The

solution was stirred at room temperature for 8 days, after which NaI

(10.8 mg, 0.072 mmol, 2.5 equiv) was added. The mixture was then

stirred at reflux temperature for an additional 2 days. The resulting

mixture was diluted with EtOAc, washed with water and brine, dried

over MgSO₄, and concentrated under reduced pressure. The product

was purified by PTLC on silica gel (eluted with 1:1 hexanes/EtOAc)

to afford 2.5 mg (11% or 19% based on recovered 46) of 47 as an

amorphous yellow solid.

1,1-Dimethylethyl 8-[[8a-[4-Hydroxy-3-methyl-2-butenyl]-2-[(4-

methoxyphenyl)methyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3-hydroxy-3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]di-

oxepino[2,3-g]indole-10-carboxylate (44). To a stirred solution of

43 (36.3 mg, 0.04 mmol, 1.0 equiv) under N₂in THF (1.0 mL) was

added n-Bu₄NF (0.12 mL, 0.12 mmol, 3.0 eq, 1.0M/THF). The solution

was heated (∼40 °C) for 3 h. At this time the solution was diluted

with water and extracted with ethyl acetate. The organic layer was

washed with brine and dried over MgSO₄. The residue was purified

by PTLC on silica gel (eluted with EtOAc) to yield 24.9 mg (79%) of

44.

¹H NMR (300 MHz) (CDCl₃): δ 1.19 (3H, s), 1.22 (3H, s), 1.52

(3H, s), 1.53 (3H, s), 1.56 (3H, s), 1.57 (3H, s), 1.59 (9H, s), 1.60 (9H,

s), 1.72-2.21 (12H, m), 2.71 (2H, br s, D₂O exch), 3.18-3.49 (4H,

1

m), 3.51 (2H, /₂ABq, J ) 14.5 Hz), 3.56 (1H, s, D₂O exch), 3.61

(1H, s, D₂O exch), 3.72 (3H, s), 3.74 (3H, s), 3.75-3.94 (6H, s), 4.18-

¹H NMR (300 MHz) (CDCl₃): δ 0.12 (6H, s), 0.14 (6H, s), 0.882

(9H, s), 0.885 (9H, s), 1.10 (3H, s), 1.13 (3H, s), 1.48 (3H, s), 1.49

(3H, s), 1.55 (3H, s), 1.56 (3H, s), 1.59 (18H, s), 1.80 (2H, dd, J )

5.7, 13.3 Hz), 1.90 (2H, dd, J ) 13.2 Hz), 2.03-2.08 (4H, m), 2.22

(2H, dd, J ) 10.4, 13.4 Hz), 2.85-2.98 (4H, m), 3.08 (2H, ¹/₂ABq, J

1

4.30 (4H, s), 4.26-4.27 (4H, m), 4.44 (2H, m), 5.25 (2H, /₂ABq, J

1

) 14.5 Hz), 5.25 (2H, /₂ABq, J ) 14.4 Hz), 6.70 (2H, d, J ) 8.7

Hz), 6.77 (2H, d, J ) 8.6 Hz), 6.83 (2H, d, J ) 8.6 Hz), 6.927 (1H, d,

J ) 8.4 Hz), 6.932 (1H, d, J ) 8.3 Hz), 7.03 (2H, d, J ) 8.6 Hz), 7.12

(1H, d, J ) 8.3 Hz), 7.15 (1H, d, J ) 8.4 Hz), 7.21 (1H, s), 7.23 (1H,

s). IR (NaCl, neat): 3422, 2976, 1753, 1649, 1513, 1496, 1457, 1371,

1333, 1251, 1153, 1033, 733 cm^-1. Mass spectrum (EI): m/e (relative

intensity) 703 (M⁺, 8), 604 (37), 603 (100). HRMS (EI): 703.3461

(C₃₉H₄₉N₃O₉requires 703.3472).

1

) 17.1 Hz), 3.29 (2H, /₂ABq, J ) 17.6 Hz), 3.56-3.62 (4H, m),

3.72 (3H, s), 3.73 (3H, s), 3.74-3.83 (2H, dd, J ) 9.4, 12.5 Hz), 3.91-

3.96 (2H, m), 4.18 (2H, dd, J ) 3.6, 12.2 Hz), 4.28 (1H, ¹/₂ABq, J )

15.9 Hz), 4.37 (1H, ¹/₂ABq, J ) 15.9 Hz), 4.54-4.74 (6H, m), 6.62-

6.75 (8H, m), 6.89-6.94 (2H, m), 6.99-7.04 (2H, m), 7.25 (1H, s),

7.28 (1H, s). IR (NaCl, neat): 2932, 1687, 1365, 1251, 1158, 1088

cm^-1. HRMS (EI): 799.4252 (C₄₅H₆₁N₃O₈Si requires 799.4228).

(R)-(E)-8a-[3-Methyl-4-oxo-2-buten-yl]hexahydropyrrolo[1,2-a]-

pyrazine-1,4-dione (49). To a stirred solution of 48 (17.25 g, 48.45

mmol, 1.0 equiv) in a 2:1 solution of CH₃CN (343 mL) and H₂O (171

mL) was added, in one portion, CAN (93 g, 170 mmol, 3.8 equiv).

After stirring for 2 h, the orange solution was poured into a large

separatory funnel and exhaustively extracted with CHCl₃. The organic

layer was washed with brine, dried over Na₂SO₄, and concentrated under

reduced pressure. The product was purified by column chromatography

(eluted with 95:4:1 CH₂Cl₂/MeOH/AcOH) to yield 9.0 g (79%) of 49

as a yellow oil. An analytical sample was obtained by PTLC (silica

gel, eluted with 1:1 hexanes/EtOAc).

1,1-Dimethylethyl 8-[[8a-[4-Chloro-3-methyl-2-butenyl]-2-[(4-

methoxyphenyl)methyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3-hydroxy-3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]di-

oxepino[2,3-g]indole-10-carboxylate (45). To 44 (24.9 mg, 0.035

mmol, 1.0 equiv) in DMF (0.35 mL) at 0 °C under Ar were added dry

LiCl (2.9 mg, 0.07 mmol, 1.9 equiv) and collidine (7 µL, 0.05 mmol,

1.5 equiv). After stirring for 10 min, methanesulfonyl chloride (4 µL,

0.05 mmol, 1.5 equiv) was added dropwise. The ice bath was removed

and the mixture stirred at room temperature for 24 h. At this time

additional collidine (2.5 equiv) and methanesulfonyl chloride (2.5 equiv)

were added, and the mixture was stirred for 2 h. It was then diluted

with water and extracted with EtOAc. The organic layer was washed

with brine, dried over MgSO₄, and concentrated to dryness. The

product was purified by PTLC on silica gel (eluted with 2:1 EtOAc/

hexanes) to yield 21.9 mg (86%) of 45 as an oil.

¹H NMR (300 MHz) (CDCl₃): δ TMS 1.76 (3H, s), 1.99-2.10 (2H,

br s), 2.17-2.26 (2H, m), 2.78 (1H, dd, J ) 7.3, 14.5 Hz), 2.90 (1H,

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

dd, J ) 8.0, 14.8 Hz), 3.54-3.63 (1H, m), 3.84 (1H, dt, J ) 12.3, 8.4

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 573

temperature overnight. The solvent was removed in Vacuo, and the

residue was purified by column chromatography (eluted with 1:2

EtOAc/hexanes) to yield 9.56 g (73%) of 52. An analytical sample

was purified by PTLC on silica gel (eluted with 1:2 EtOAc/hexanes)

to give a white crystalline solid, mp 106-108 °C.

1

Hz), 3.95 (1H, d /₂ABq, J ) 3.4, 17.6 Hz), 4.10 (1H, /₂ABq, J )

17.6 Hz), 6.55 (1H, t, J ) 7.2 Hz), 7.96 (1H, br s, D₂O exch), 9.45

(1H, s). IR (NaCl, neat): 3246, 1684, 1448, 1326, 1107 cm^-1. [R]²⁵

D

) -1.51/1.92 × 10^-2)° ) -78.4° (CH₂Cl₂, c ) 0.164). Microanal.

Calcd: C, 61.00; H, 6.83; N, 11.86. Found: C, 60.88; H, 6.66; N,

11.71. HRMS (EI): 236.1155 (C₁₂H₁₆N₂O₃requires 236.11609).

(R)-(E)-8a-[4-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3-methyl-2-

butenyl]hexahydro-2H-pyrrolo[1,2-a]pyrazine-1,4-dione (50). To a

stirred solution of 49 (9.0 g, 37 mmol, 1.0 equiv) in absolute ethanol

(742 mL) at room temperature was added NaBH₄(2.85 g, 75.5 mmol,

2.0 equiv). After 2 h the excess hydride was quenched with water

(500 mL) and the pH adjusted to 3-4 by the slow addition of 1 M

HCl. Fifteen minutes later, the water and ethanol were removed under

reduced pressure and the crude residue was dried in vacuo overnight.

The resulting mass (10.87 g) was triturated (1:4 CH₃OH/CH₂Cl₂) and

filtered to remove the salts. The remaining solution was concentrated

to yield 9.1 g of the crude allylic alcohol, which was immediately

utilized for the next step without additional purification. The crude

allylic alcohol (9.1 g, 38 mmol, 1.0 equiv) was dissolved in DMF (191

mL) under Ar, and to this mixture was added imidazole (11.9 g, 175.3

mmol, 4.6 equiv) followed by tert-butyldiphenylsilyl chloride (12.9 mL,

49.5 mmol, 1.3 equiv). After 2 days the reaction mixture was diluted

with water (1 L) and extracted with a 1:1 solution of hexanes and

EtOAc. The organic layer was washed with brine, dried over Na₂SO₄,

and concentrated to dryness. The crude solid was recrystallized (ethyl

acetate, two crops) to give 10.5 g of the product. The remaining mother

liquor was chromatographed (eluted with EtOAc) to give 3.0 g of the

pure product. Total yield of 50: 13.5 g (75% from the enone, two

steps). An analytical sample was recrystallized from acetone to provide

a white crystalline solid, mp 132 °C.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.10 (6H, s), 0.115 (3H, s), 0.12 (3H, s), 0.87 (9H, s), 0.88 (9H, s),

1.02 (18H, s), 1.096 (3H, s), 1.10 (3H, s), 1.45 (3H, s), 1.46 (3H, s),

1.54 (6H, s), 1.60-1.88 (6H, m), 2.02-2.11 (2H, m): 2.92 (2H, dd, J

) 7.1, 14.4 Hz), 2.44 (2H, dd, J ) 8.1, 14.5 Hz), 3.32-3.44 (4H, m),

3.60 (3H, s), 3.62 (3H, s), 3.72-3.93 (8H, m), 3.98 (4H, br s), 4.18

(2H, dd, J ) 2.9, 8.4 Hz), 5.43 (2H, m), 6.38 (1H, s, D₂O exch), 6.41

(1H, s, D₂O exch), 6.74 (1H, d, J ) 8.5 Hz), 6.75 (1H, d, J ) 8.5 Hz),

6.89 (1H, d, J ) 2.3 Hz), 6.92 (1H, d, J ) 2.3 Hz), 7.08 (2H, d, J )

8.5 Hz), 7.33-7.41 (12H, m), 7.61-7.63 (8H, m), 8.43 (1H, d, J )

2.9 Hz, D₂O exch), 8.64 (1H, d, J ) 1.9 Hz, D₂O exch.). ¹³C NMR

(75.5 MHz) (CDCl₃) (mixture of two diastereomers): δ 4.8, 4.2, 9.5,

17.9, 19.2, 19.3, 19.5, 20.3, 25.7, 26.8, 28.0, 28.3, 29.7, 33.7, 35.6,

46.1, 46.2, 53.3, 66.9, 68.0, 71.6, 76.3, 80.7, 80.8, 108.2, 112.9, 117.1,

117.9, 118.0, 123.5, 123.6, 125.5, 127.6, 129.1, 129.2, 129.6, 133.6,

135.5, 138.8, 141.6, 141.8, 161.4, 169.7, 170.5, 170.6. IR (NaCl,

neat): 3281 (br), 2954, 2932, 2856, 1747, 1670, 1665, 1649, 1431,

1251, 1224, 1109, 1088, 733, 706 cm^-1

. HRMS (EI): 893.4457

(C₅₀H₆₇N₃O₈Si₂requires 893.4467). Microanal. Calcd for C₅₀H₆₇-

N₃O₈Si₂: C, 67.16; H, 7.55; N, 4.70. Found: C, 66.93; H, 7.36; N,

4.51.

[3â,8aâ(E)]-8-[[8a-[4-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3-

methyl-2-butenyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-3-yl]

methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-

dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole (53). [3r,8aâ(E)] 8-[[8a-

[4-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3-methyl-2-butenyl]oc-

tahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-

dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-

[1,4]dioxepino[2,3-g]indole (54). A flask containing 52 (9.56 g, 10.7

mmol, 1.0 equiv) and LiCl (2.26 g, 53.45 mmol, 5.0 equiv) under Ar

was charged with HMPA (82 mL) and water (0.29 mL, 16.0 mmol,

1.5 equiv). This mixture was gently heated (100-105 °C) for 9 h and

then diluted with 1:1 hexanes/EtOAc. The resulting solution was

washed with water. The organic layer was washed with brine, dried

over Na₂SO₄, and evaporated to dryness. The residue was purified by

column chromatography (eluted with 1:2 EtOAc/hexanes) to yield 5.90

g (66%) of 53 (two diastereomers; an analytical sample was recrystal-

lized from CCl₄, mp (syn) 167-168 °C) and 2.10 g (23%) of 54 (two

diastereomers); an analytical sample was obtained by PTLC on silica

gel (eluted with 1:2 EtOAc/hexanes, mp (anti) 95-99 °C, white

crystalline solid). Total combined yield: 8.00 g (89%).

¹H NMR (300 MHz) (CDCl₃) (53, mixture of two diastereomers):

δ TMS 0.12 (6H, s), 0.13 (6H, s), 0.90 (18H, s), 1.0 (18H, s), 1.126

(3H, s), 1.13 (3H, s), 1.48 (6H, s), 1.64 (6H, s), 1.94-2.06 (6H, m),

2.20-2.24 (2H, m), 2.36-2.46 (2H, m), 2.60-2.72 (2H, m), 2.98 (2H,

dd, J ) 11.6, 14.1 Hz), 3.44-3.57 (4H, m), 3.88 (2H, dd, J ) 6.7, 9.2

Hz), 3.97 (2H, dd, J ) 3.1, 9.1 Hz), 4.02-4.06 (2H, m), 4.10 (4H, s),

4.17-4.25 (4H, m), 5.58 (2H, m), 5.68 (2H, br s, D₂O exch), 6.75

(2H, d, J ) 8.5 Hz), 6.86 (1H, d, J ) 2.2 Hz), 6.88 (1H, J ) 2.2 Hz),

7.14 (2H, d, J ) 8.4 Hz), 7.26-7.44 (12H, m), 7.60-7.64 (8H, m),

8.04 (1H, s, D₂O exch), 8.06 (1H, s, D₂O exch).

¹H NMR (300 MHz) (CDCl₃): δ 1.03 (9H, s), 1.54 (3H, s), 1.92-

2.19 (4H, m), 2.49 (1H, dd, J ) 8.6, 14.1 Hz), 2.58 (1H, dd, J ) 7.5,

14.1 Hz), 3.44-3.53 (1H, m), 3.73 (1H, d ¹/₂ABq, J ) 4.1, 16.9 Hz),

1

3.78-3.85 (1H, m), 4.01 (2H, s), 4.06 (1H, /₂ABq, J ) 16.9 Hz),

5.56-5.62 (1H, m), 6.38 (1H, d, J ) 3.7 Hz, D₂O exch), 7.32-7.43

(6H, m), 7.62 (4H, dd, J ) 1.8, 7.6 Hz). IR (NaCl, neat): 3232 (br),

2930, 2857, 1664, 1446, 1435, 1113, 822, 733, 702 cm^-1. [R]²⁵

)

D

-63.3° (CDCl₃, c ) 0.0822). Microanal. Calcd for C₂₈H₃₆N₂O₃Si:

C,70.55; H, 7.61; N, 5.88. Found C, 70.60; H, 7.56; N, 5.91.

[(R)-[3râ,8aâ(E)]]-Methyl 8a-[4-[[(1,1-Dimethylethyl)diphenyl-

silyl]oxy]-3-methyl-2-butenyl]octahydro-2-(methoxycarbonyl)-1,4-

dioxopyrrolo[1,2-a]pyrazine-3-carboxylate (51). To a stirred solution

of 50 (8.12 g, 17.0 mmol, 1.0 equiv) in THF (208 mL) at -78 °C, was

added a solution of n-BuLi (10.65 mL, 17.03 mmol, 1.0 equiv, 1.6

M/hexanes) dropwise. After 25 min methyl chloroformate (1.45 mL,

18.7 mmol, 1.1 equiv) was added dropwise to the reaction mixture

and stirred for 25 min. The solution was then transferred via cannula

to a cold (-100 °C) flask charged with LiN[Si(CH₃)₃]₂(37.47 mL,

37.47 mmol, 2.2 equiv, 1.0 M/THF) and methyl chloroformate (1.45

mL, 18.7 mmol, 1.1 equiv). The resulting solution was stirred for 45

min, diluted with EtOAc, and washed with saturated aqueous NH₄Cl

and brine. The organic layer was dried over MgSO₄and concentrated

under reduced pressure. The residue was purified by flash column

chromatography (eluted with 2:1 hexanes/EtOAc) to yield 9.4 g (93%)

of 51 (as a mixture of two diastereomers, anti/syn). An analytical

sample (oil) was obtained by PTLC (eluted with 2:1 hexanes/EtOAc).

¹H NMR (300 MHz) (CDCl₃): δ 1.04 (9H, s), 1.40 (3H, s), 1.86-

2.03 (2H, m), 2.12-2.31 (2H, m), 2.55 (1H, d, J ) 7.4 Hz), 3.43-

3.52 (2H, m), 3.74-3.82 (1H, m), 3.83 (3H, s), 3.88 (3H, s), 4.03 (2H,

br s), 5.48-5.53 (2H, m), 7.34-7.41 (6H, m), 7.57-7.66 (4H, m). IR

(NaCl, neat): 2960, 1790, 1740, 1681, 1430, 1366, 1272, 1223, 1109,

735, 705 cm^-1. Microanal. Calcd for C₃₂H₄₀N₂O₇Si: C, 68.06; H,

7.14; N, 4.96. Found: C, 67.87; H, 7.27; N, 4.77.

The analytical samples of the syn-diastereomers were separable by

PTLC.

¹H NMR (300 MHz) (CDCl₃) (53a, less polar): δ TMS 0.12 (3H,

s), 0.13 (3H, s), 0.88 (9H, s), 1.03 (9H, s), 1.11 (3H, s), 1.46 (3H, s),

1.63 (3H, s), 1.92-2.04 (3H, m), 2.18-2.23 (1H, m), 2.39 (1H, dd, J

) 7.2, 14.2 Hz), 2.64 (1H, dd, J ) 8.7, 14.2 Hz), 2.99 (1H, dd, J )

11.4, 14.2 Hz), 3.42-3.46 (1H, m), 3.51 (1H, dd, J ) 2.7, 14.2 Hz),

3.85 (1H, dd, J ) 9.2, 11.3 Hz), 3.94 (1H, dd, J ) 3.0, 9 Hz), 3.99-

4.06 (1H, m), 4.08 (2H, s), 4.11-4.15 (1H, m), 4.19 (1H, dd, J ) 3.0,

11.3 Hz), 5.58 (1H, t, J ) 7.8 Hz), 5.76 (1H, d, J ) 2.7 Hz, D₂O

exch), 6.73 (1H, d, J ) 8.4 Hz), 6.85 (1H, d, J ) 2.1 Hz), 7.11 (1H,

d, J ) 8.5 Hz), 7.26-7.42 (6H, m), 7.57-7.63 (4H, m), 8.15 (1H, s,

D₂O exch).

[3â,8aâ(E)]-Methyl 3-[[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-

3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indol-8-yl]

methyl]-8a-[4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-3-methyl-2-

butenyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazine-3-carboxylate (52).

To a flask containing 51 (5.89 g, 14.56 mmol, 1.0 equiv) and 36 (8.64

g, 14.56 mmol, 1.1 equiv) were added CH₃CN (291 mL) and

tributylphosphine (1.82 mL, 7.28 mmol, 0.5 equiv). The resulting

mixture was gently refluxed for 3.5 h and then stirred at room

¹H NMR (300 MHz) (CDCl₃) (53b, more polar): δ TMS 0.12 (3H,

s), 0.14 (3H, s), 0.88 (9H, s), 1.03 (9H, s), 1.11 (3H, s), 1.46 (3H, s),

1.62 (3H, s), 1.91-2.04 (3H, m), 2.18-2.22 (1H, m), 2.36 (1H, dd, J

574 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

) 7.3, 14.2 Hz), 2.60 (1H, dd, J ) 8.6, 14.3 Hz), 2.97 (1H, dd, J )

11.3, 14.2 Hz), 3.41-3.44 (1H, m), 3.50 (1H, dd, J ) 3.1, 14.2 Hz),

3.86 (1H, dd, J ) 9.3, 11.3 Hz), 3.95 (1H, dd, J ) 3.0, 9.1 Hz), 3.99-

4.03 (1H, m), 4.08 (2H, s), 4.14-4.16 (1H, m), 4.20 (1H, dd, J ) 2.9,

11.6 Hz), 5.56 (1H, t, J )7.5 Hz), 5.72 (1H, d, J ) 2.6 Hz, D₂O exch),

6.73 (1H, d, J ) 8.4 Hz), 6.84 (1H, d, J ) 2.1 Hz), 7.11 (1H, d, J )

8.4 Hz), 7.26-7.42 (6H, m), 7.57-7.62 (4H, m), 8.07 (1H, s, D₂O

exch). IR (NaCl, neat) (syn): 3274 (br), 2929, 2858, 1666, 1651, 1453,

1428, 1250, 1224, 1112, 1052, 858, 838, 777 cm^-1. Microanal. Calcd

for C₄₉H₆₅N₃O₆Si₂(syn): C, 68.94; H, 7.84; N, 5.02. Found: C, 69.06;

H, 7.76; N, 5.03.

with EtOAc) to yield 369 mg (89%) of the diol (obtained as a pale

yellow, amorphous solid).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.21 (3H, s), 1.24 (3H, s), 1.29 ((9H, s), 1.35 (9H, s), 1.47 (6H, s),

1.52 (6H, s), 1.56 (18H, s), 1.63-2.21 (14H, m), 3.21-3.38 (8H, m),

3.54 (1H, br s, D₂O exch), 3.58 (1H, br s, D₂O exch), 3.81-3.87 (6H,

m, 2H D₂O exch), 4.22 (4H, d, J ) 8.0 Hz), 4.62 (1H, t, J ) 8.4 Hz),

4.96-5.01 (2H, m), 5.07 (1H, t, J ) 7.2 Hz), 6.90 (1H, d, J ) 8.4

Hz), 6.91 (1H, d, J ) 8.4 Hz), 7.13 (1H, d, J ) 8.4 Hz), 7.18 (1H, d,

J ) 8.4 Hz), 7.22 (1H, s), 7.23 (1H, s). IR (NaCl, neat): 3436, 2978,

1755, 1649, 1367, 1249, 1149, 732 cm^-1

.

¹H NMR (300 MHz) (CDCl₃) (54, mixture of two diastereomers):

δ TMS 0.14 (6H, s), 0.16 (6H, s), 0.90 (18H, s), 1.04 (9H, s), 1.045

(9H, s), 1.09 (3H, s), 1.13 (3H, s), 1.47 (6H, s), 1.53 (3H, m), 1.54

(3H, m), 1.97-2.17 (8H, m), 2.47-2.62 (4H, m), 2.78-2.88 (2H, m),

3.54-3.65 (4H, m), 3.82-3.99 (6H, m), 4.02 (4H, s), 4.21 (2H, dd, J

) 3.1, 11.0 Hz), 4.35-4.39 (2H, m), 5.52-5.54 (2H, m), 5.69 (2H, br

s, D₂O exch), 6.60 (2H, d, J ) 8.4 Hz), 6.63 (2H, d, J ) 8.4 Hz), 6.89

(2H, d, J ) 2.1 Hz), 6.98 (2H, d, J ) 8.4 Hz), 7.36-7.42 (10H, m),

7.62-7.69 (8H, m), 8.08 (2H, br s, D₂O exch). IR (NaCl, neat) (anti):

3289 (br), 2929, 2855, 1666, 1444, 1428, 1254, 1222, 1111, 857, 836,

704 cm^-1. Mass spectrum (EI) (anti): m/e (relative intensity) 833 (M⁺,

0.1), 512 (6.4), 361 (26), 360 (100), 199 (47). Microanal. Calcd for

C₄₈H₆₅N₃O₆Si₂(anti): C, 68.94; H, 7.84; N, 5.02. Found: C, 68.76;

H, 7.60; N, 4.82.

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[2-[(1,1-Dimethylethoxy)carbo-

nyl]-8a-[4-chloro-3-methyl-2-butenyl]octahydro-1,4-dioxopyrrolo-

[1,2-a]pyrazin-3-yl]methyl]-3,4-dihydro-4,4-dimethyl-3-hydroxy-

2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate. To a stirred

solution of the diol obtained above (50.0 mg, 0.0725 mmol, 1.0 equiv)

in DMF (0.73 mL) at 0 °C under Ar were added collidine (0.014 mL,

0.11 mmol, 1.5 equiv) and LiCl (5.27 mg, 0.12 mmol, 1.7 equiv). After

15 min, MsCl (8.4 µL, 0.11 mmol, 1.5 equiv) was added and the

reaction mixture allowed to reach room temperature in the course of

16 h. At this time an additional amount (1.0 equiv) of each reagent

was added in the same manner as above. After 8.5 h there was little

change by TLC, so a large excess of MsCl (0.06 mL, 0.775 mmol,

10.7 equiv) was added at 0 °C and stirred for ∼12 h until only the

desired product was apparent by TLC. The solution was diluted with

1:1 hexanes/EtOAc, washed with water and brine, dried over MgSO₄,

and concentrated, under reduced pressure. The residue was purified

by radial chromatography, 1:1 EtOAc/hexanes, to yield 45.5 mg (91%)

of the product allylic chloride (obtained as a foamy glass).

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[2-[(1,1-Dimethylethoxy)carbo-

nyl]-8a-[4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-3-methyl-2-bute-

nyl]octahydro-1,4-dioxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-

dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-

[1,4]dioxepino[2,3-g]indole-10-carboxylate (58). To a stirred solution

of 53 (310 mg, 0.37 mmol, 1.0 equiv) at 0 °C under Ar in CH₂Cl₂(7.4

mL) were added Et₃N (0.1 mL, 0.74 mmol, 2.0 equiv) and DMAP

(90.7 mg, 0.74 mmol, 2.0 equiv). After 5 min, (BOC)₂O (486.2 mg,

2.2 mmol, 6.0 equiv) was added in one portion. The resulting solution

was stirred for 8.5 h, poured into water, and extracted with EtOAc.

The organic layer was washed with 10% CuSO₄and brine, dried over

MgSO₄, and concentrated under reduced pressure. The residue was

purified by radial chromatography (eluted with 1:2 EtOAc/hexanes) to

yield 375 mg (97%) of 58 as an amorphous solid.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.18 (3H, s), 1.20 (3H, s), 1.24 (9H, s), 1.30 (9H, s), 1.51 (3H, s), 1.54

(3H, s), 1.58 (18H, s), 1.64 (3H, s), 1.66 (3H, s), 1.74-2.18 (10H, m),

2.27 (2H, dd, J ) 8.1, 15.0 Hz), 3.02 (2H, br s, D₂O exch), 3.19 (2H,

dd, J ) 7.2, 14.8 Hz), 3.27-3.44 (4H, m), 3.56 (2H, br s), 3.81-3.89

(2H, m), 3.91 (2H, s), 3.94 (2H, s), 4.18-4.30 (4H, m), 4.99-5.06

(2H, m), 5.21 (1H, t, J ) 8.3 Hz), 5.38-5.43 (1H, m), 6.93 (2H, d, J

) 8.3 Hz), 7.17 (1H, d, J ) 8.3 Hz), 7.20 (1H, d, J ) 8.3 Hz), 7.21

(1H, s), 7.24 (1H, s). IR (NaCl, neat): 3384, 2920, 1750, 1736, 1657,

1367, 1250, 1149 cm^-1

.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.12 (6H, s), 0.13 (6H, s), 0.879 (9H, s), 0.880 (9H, s), 1.01 (18H, s),

1.05 (3H, s), 1.07 (3H, s), 1.14 (9H, s), 1.18 (9H, s), 1.55 (6H, s), 1.47

(6H, s), 1.57 (18H, s), 1.88-2.16 (6H, m), 2.17-2.26 (2H, m), 2.28-

2.36 (2H, m), 2.50 (2H, dd, J ) 8.1, 14.5 Hz), 3.22 (2H, m), 3.32-

3.45 (4H, m), 3.71-3.81 (2H, m), 3.84-3.96 (4H, m), 4.00 (4H, br s),

4.13-4.18 (2H, m), 5.02-5.07 (2H, m), 5.42 (1H, t, J ) 7.3 Hz), 5.53

(1H, t, J ) 7.5 Hz), 6.91 (2H, d, J ) 8.3 Hz), 7.16 (1H, d, J ) 8.0

Hz), 7.19 (1H, d, J ) 8.2 Hz),7.22 (1H, s), 7.24 (1H, s), 7.30-7.40

(12H, m), 7.57-7.61 (8H, m). IR (NaCl, neat): 2932, 1752, 1730,

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[2-[(1,1-Dimethylethoxy)carbo-

nyl]-8a-[4-chloro-3-methyl-2-butenyl]octahydro-1,4-dioxopyrrolo-

[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole-

10-carboxylate (55). To a stirred solution of the allylic chloride

obtained above (96.2 mg, 0.37 mmol, 1.0 equiv) in CH₂Cl₂(0.5 mL)

under Ar were added 2,6-lutidine (0.016 mL, 0.14 mmol, 0.38 equiv)

and tert-butyldimethylsilyl triflate (0.03 mL, 0.14 mmol, 0.38 equiv).

After 1 h an additional amount (0.5 equiv) of the two reagents was

added. The mixture was stirred for 1 h, and another portion (0.5 equiv)

of each reagent was added. The solution was stirred for 75 min and

was then poured into water and extracted with EtOAc. The organic

layer was washed with brine, dried over MgSO₄, and concentrated under

reduced pressure. The residue was purified by radial chromatography

(eluted with 1:2 EtOAc/hexanes) to yield 106.5 mg (99%) of 55 as a

white crystalline solid, mp 70-73 °C.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.10 (3H, s), 0.11 (6H, s), 0.12 (3H, s), 0.877 (18H, s), 1.04 (3H, s),

1.06 (3H, s), 1.22 (9H, s), 1.29 (9H, s), 1.44 (3H, s), 1.46 (3H, s), 1.58

(18H, s), 1.62 (3H, s), 1.65 (3H, s), 1.76-2.13 (10H, m), 2.22 (2H,

dd, J ) 8.4, 14.8 Hz), 3.19 (2H, dd, J ) 7.1, 14.7 Hz), 3.26-3.42

(4H, m), 3.68-3.78 (2H, m), 3.81-3.87 (4H, m), 3.90 (2H, s), 3.94

(2H, s), 4.10-4.17 (2H, m), 5.00-5.05 (2H, m), 5.22 (1H, t, J ) 7.6

Hz), 5.41 (1H, t, J ) 7.6 Hz), 6.91 (2H, d, J ) 8.3 Hz), 7.14 (1H, d,

J ) 8.3 Hz), 7.16 (1H, d, J ) 8.3 Hz), 7.21 (1H, s), 7.24 (1H, s). ¹³C

NMR (75.5 MHz) (CDCl₃) (mixture of two diastereomers): δ -5.0,

-4.1, -4.0, 14.3, 17.8, 18.3, 19.7, 19.8, 25.6 27.3, 27.4, 27.9, 28.5,

29.6, 30.1, 34.5, 34.7, 36.1, 45.2, 45.32, 51.3, 51.4, 60.5, 68.1, 68.2,

70.9, 70.9, 75.7, 80.2, 83.1, 84.2, 84.2, 113.6, 113.8, 114.1, 114.2, 120.0,

120.1, 122.6, 122.7, 126.9, 127.1, 127.8, 127.9, 129.0, 135.6, 135.8,

140.43, 146.3, 146.4, 148.3, 148.4, 150.3, 150.5, 164.4, 164.5, 168.6,

168.7. IR (NaCl, neat): 2936, 1754, 1729, 1663, 1496, 1456, 1370,

1660, 1371, 1251, 1153, 1109, 1088, 706 cm^-1

1035.5481 (C₅₈H₈₁N₃O₁₀Si₂requires 1035.5461).

. HRMS (EI):

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[2-[(1,1-Dimethylethoxy)carbo-

nyl]-8a-[4-hydroxy-3-methyl-2-butenyl]octahydro-1,4-dioxopyrrolo-

[1,2-a]pyrazin-3-yl]methyl]-3,4-dihydro-4,4-dimethyl-3-hydroxy-

2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate. To a stirred

solution of 53 (511 mg, 0.61 mmol, 1.0 equiv) at 0 °C under Ar in

CH₂Cl₂(12.2 mL) were added DMAP (149.4 mg, 1.2 mmol, 2.0 equiv)

and Et₃N (0.17 mL, 1.2 mmol, 2.0 equiv). After 5 min, (BOC)₂O (801.0

mg, 3.67 mmol, 6.0 equiv) was added in one portion. The resulting

solution was stirred for 2.7 h, and reaction was found to be complete

by TLC analysis; during this period, the reaction temperature slowly

reached 15 °C. The reaction flask was then charged with THF (12

mL) and the CH₂Cl₂removed by evaporation (until the volume of the

flask was approximately 12 mL). The solution was stirred at room

temperature and n-Bu₄NF (1.96 mL, 1.96 mmol, 3.2 eq, 1.0 M/THF)

added quickly. After 22 h, additional n-Bu₄NF (1.0 mL, 1.0 mmol,

1.6 equiv, 1.0 M/THF) was added to the reaction flask and stirred for

24 h. The reaction was complete by TLC and was poured into water

and extracted with EtOAc. The organic layer was washed with 10%

CuSO₄and brine, dried over MgSO₄, and concentrated under reduced

pressure. The residue was purified by radial chromatography (eluted

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 575

1248, 1152, 1086, 838 cm^-1. HRMS (EI): 815.3973 (C₄₂H₆₂N₃O₉-

SiCl requires 815.3944).

poured into water and extracted with EtOAc. The organic layer was

washed with brine, dried over Na₂SO₄, and concentrated to dryness

under reduced pressure. The residue was purified by column chro-

matography (eluted with 1:2 EtOAc/hexanes) to yield 5.30 g (62%) of

61. [The yield of 61 was 365 mg (71%) from 508 mg of 54.] An

analytical sample was obtained by PTLC on silica gel (eluted with 1:2

EtOAc/hexanes and obtained as a white crystalline solid, mp 54-58

°C).

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[8a-[4-[[(1,1-Dimethylethyl)-

diphenylsilyl]oxy]-3-methyl-2-butenyl]octahydro-1,4-dioxopyrrolo-

[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]-

oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole-

10-carboxylate (59). To a flask fitted with a reflux condenser was

added 58 (799 mg, 0.771 mmol, 1.0 equiv) followed by CH₃CN (15.4

mL) and dimethylamine (0.53 mL, 3.85 mmol, 5.0 equiv, 40% solution

in water). The resulting solution was refluxed for 2 h and 20 min.

The solvent was removed under reduced pressure and the residue

purified by radial chromatography (eluted with 1:2 EtOAc/hexanes) to

yield 657 mg (92%) of 59. An analytical sample was obtained by

PTLC, on silica gel (eluted with 1:2 EtOAc/hexanes) (foamy oil).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.14 (6H, s), 0.23 (6H, s), 0.88 (18H, s), 1.01 (18H, s), 1.10 (6H, s),

1.48 (6H, d), 1.59 (18H, s), 1.62 (6H, s), 1.98-2.05 (6H, m), 2.07-

2.19 (2H, m), 2.37-2.47 (2H, m), 2.64-2.75 (2H, m), 2.94 (2H, dd,

J ) 11.6, 14.1 Hz), 3.41-3.47 (4H, m), 3.82 (2H, dd, J ) 9.6, 12.2

Hz), 3.93-4.03 (4H, m), 4.07 (4H, br s), 4.10-4.15 (2H, m), 4.20

(2H, dd, J ) 2.7, 12.4 Hz), 5.56-5.61 (2H, m), 5.78 (1H, d, J ) 3.0

Hz, D₂O exch), 5.81 (1H, d, J ) 2.8 Hz, D₂O exch), 6.877 (1H, d, J

) 8.4 Hz), 6.884 (1H, d, J ) 8.4 Hz), 7.09 (2H, d, J ) 8.4 Hz), 7.20-

7.40 (14H, m), 7.56 - 7.61 (8H, m). ¹³C NMR (75.5 MHz) (CDCl₃)

(mixture of two diastereomers): δ -5.0, -4.1, 13.7, 14.0, 17.8, 18.6,

18.8, 19.1, 19.6, 22.5, 25.7, 26.7, 28.0, 28.4, 28.4, 31.4, 31.6, 31.7,

34.9, 35.8, 44.81, 57.5, 67.5, 68.2, 71.0, 75.8, 76.6, 77.0, 77.4, 80.3,

83.3, 83.1, 113.3, 114.6, 116.6, 120.1, 126.3, 126.3, 127.5 127.6, 128.1,

128.2, 128.4, 128.4, 128.6, 133.1, 133.2, 135.4, 139.2, 140.5, 140.6,

146.4, 146.5, 148.4, 164.4, 169.6, 169.7. IR (NaCl, neat): 3246, 2960

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.13 (3H, s), 0.14 (9H, s), 0.89 (18H, s), 1.03 (9H, s), 1.04 (9H, s),

1.087 (3H, s), 1.093 (3H, s), 1.28-1.43 (4H, m), 1.48 (6H, s), 1.50

(6H, s), 1.79-1.89 (4H, m), 2.24-2.38 (4H, m), 3.22-3.42 (6H, m),

3.60 (3H, s), 3.62 (3H, s), 3.68-3.76 (2H, m), 3.79-3.87 (2H, m),

3.94 (2H, d, J ) 3.4 Hz), 3.97 (4H, br s), 4.15-4.20 (2H, m), 4.26-

4.32 (2H, m), 5.41 (2H, t, J ) 7.8 Hz), 6.701 (1H, d, J ) 8.5 Hz),

6.703 (1H, d, J ) 8.4 Hz), 6.96 (1H, d, J ) 2.6 Hz), 6.97 (1H, d, J )

2.6 Hz), 7.28 (2H, d, J ) 8.5 Hz), 7.32-7.44 (12H, m), 7.60-7.64

(8H, m), 7.97 (2H, br s, D₂O exch). IR (NaCl, neat): 3304, 2930,

1695, 1645, 1447, 1249, 1221, 836 cm^-1

. HRMS (EI): 849.4550

(C₄₉H₆₇N₃O₆Si₂requires 849.4568). Microanal. Calcd for C₄₉H₆₇-

N₃O₆Si₂: C, 69.22; H, 7.94; N, 4.94. Found: C, 59.06; H, 8.04; N,

4.89.

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-(4-

hydroxy-3-methyl-2-butenyl)-1-methoxy-4-oxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3,4-dihydro-3-hydroxy-4,4-dimethyl-2H,10H-[1,4]di-

oxepino[2,3-g]indole-10-carboxylate (62). To stirred solution of 60

(5.45 g, 6.41 mmol, 1.0 equiv) in CH₂Cl₂(32 mL) under Ar at 0 °C

were added Et₃N (0.89 mL, 6.41 mmol, 1.0 equiv) and DMAP (783.1

mg, 6.41 mmol, 1.0 equiv). After 10 min (BOC)₂O (4.20 g, 19.2 mmol,

3.0 equiv) was added in one portion. The reaction mixture was stirred

for 6 h and diluted with THF (45 mL). The remaining CH₂Cl₂was

removed by evaporation under reduced pressure (until the volume in

the flask was 45 mL). The flask was charged with n-Bu₄NF (19.2

mL, 19.2 mmol, 3.0 equiv, 1.0 M/THF), and the mixture was stirred at

room temperature for approximately 12 h. The solution was diluted

with water and extracted with EtOAc. The organic layer was washed

with brine, dried over Na₂SO₄, and concentrated to dryness under

reduced pressure. The residue was purified by column chromatography

(eluted with 1:2 EtOAc/hexanes; then 2:1 EtOAc/hexanes) to yield 3.45

g (90%) of 62. [The yield of 62 was 243 mg (97%) from 355 mg of

60.] An analytical sample was obtained by PTLC on silica gel (eluted

with 2:1 EtOAc/hexanes) to afford a white solid, mp 72-85 °C.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.18 (6H, s), 1.52 (3H, s), 1.53 (3H, s), 1.56 (3H, s), 1.57 (21H, s),

1.61-2.07 (10H, m), 2.14 (2H, dd, J ) 8.6, 14.5 Hz), 2.85 (2H, br s,

D₂O exch), 2.92-3.01 (2H, m), 3.18-3.35 (6H, m), 3.56 (2H, br s,

D₂O exch), 3.62 (3H, s), 3.64 (3H, s), 3.88 (4H, br s), 3.91-4.00 (2H,

m), 4.25 (4H, br s), 4.30-4.39 (2H, m), 4.98-5.01 (2H, m), 6.87 (1H,

d, J ) 8.3 Hz), 6.88 (1H, d, J ) 8.3 Hz), 7.16 (1H, d, J ) 8.3 Hz),

7.17 (1H, d, J ) 8.3 Hz), 7.34 (1H, s), 7.35 (1H, s). ¹³C NMR (75.5

MHz) (CDCl₃) (mixture of two diastereomers): δ 13.4, 19.5, 19.7, 23.5,

23.6, 25.1, 25.3, 27.9, 30.3, 30.5, 34.4, 34.8, 35.1, 35.3, 43.4, 43.6,

52.6, 52.7, 62.0, 62.4, 65.3, 65.4, 67.7, 67.8, 70.6, 75.4, 82.6, 82.6,

114.5, 114.7, 116.8, 116.9, 118.2, 118.3 119.0, 119.1, 126.3, 128.0,

128.1, 129.9 130.0, 138.6, 138.7, 140.7, 146.2, 148.5, 161.32, 161.5,

168.5, 168.7 IR (NaCl, neat): 3390 (br), 2976, 1752, 1692, 1632, 1491,

2861, 1750, 1676, 1662, 1430, 1366, 1252, 1159, 1109, 1090 cm^-1

.

HRMS (EI): 935.48955 (C₅₃H₇₃N₃O₈Si₂requires 935.4936). Microanal.

Calcd for C₅₃H₇₃N₃O₈Si₂: C, 67.57; H, 7.96; N, 4.54. Found: C, 67.62;

H, 7.94; N, 4.32.

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-[4-

[[(1,1-dimethylethyl)diphenylsilyl]oxy]-3-methyl-2-butenyl]-1-meth-

oxy-4-oxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-dimethylethyl)-

dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-

[1,4]dioxepino[2,3-g]indole-10-carboxylate (60). To a stirred solution

of 53 (3.87 g, 4.63 mmol, 1.0 equiv) in CH₂Cl₂(46 mL) under Ar at

0 °C was added Na₂CO₃(9.8 g, 92.6 mmol, 20.0 equiv). After 10

min, Me₃OBF₄(3.42 g, 23.15 mmol, 5.0 equiv) was added in one

portion. The mixture was stirred for 4.0 h at room temperature, poured

into water, and extracted with EtOAc. The organic layer was washed

with brine, dried over Na₂SO₄, and concentrated to dryness under

reduced pressure. The residue was purified by flash column chroma-

tography (eluted with 1:2 hexanes/EtOAc; then 1:1 hexanes/EtOAc)

to yield 3.20 g (81%) of 60. An analytical sample was obtained by

PTLC on silica gel (eluted with EtOAc) (isolated as a white solid, mp

74-76 °C).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.120 (12H, s), 0.875 (18H, s), 1.02 (18H, s), 1.06 (3H, s), 1.07 (3H,

s), 1.45 (12H, s), 1.65-2.08 (14H, m), 3.07-3.15 (2H, m), 3.26 (2H,

dd, J ) 6.2, 12.6 Hz), 3.32-3.40 (2H, m), 3.61 (6H, s), 3.70-3.86

(2H, m), 3.91-3.95 (4H, m), 3.99 (2H, s), 4.15 (2H, dd, J ) 3.6, 11.7

Hz), 4.36-4.40 (2H, m), 5.37-5.44 (2H, br m), 6.69 (2H, d, J ) 8.4

Hz), 7.01 (2H, d, J ) 1.7 Hz), 7.15 (2H, d, J ) 8.4 Hz), 7.26-7.41

(12H, m), 7.58-7.62 (8H, m), 8.06 (2H, s, D₂O exch). IR (NaCl,

1453, 1371, 1251, 1158, 733 cm^-1

. Microanal. Calcd for C₃₂H₄₃-

N₃O₈: C, 64.30; H, 7.25; N, 7.03. Found: C, 64.12; H, 7.41; N, 6.88.

HRMS (EI): m/e 597.3065 (C₃₂H₄₃N₃O₈requires 597.3050).

neat): 3292, 2932, 1687, 1643, 1447, 1251, 1218, 1109, 837 cm^-1

.

Mass spectrum (EI): m/e (relative intensity) 849 (M⁺, 8.9), 361 (26),

360 (95), 167 (100). Microanal. Calcd for C₄₉H₆₇N₃O₆Si₂: C, 69.02;

H, 7.94; N, 4.94. Found: C, 69.02; H, 7.88; N, 4.79.

[3r,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-(4-

hydroxy-3-methyl-2-butenyl)-1-methoxy-4-oxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3,4-dihydro-3-hydroxy-4,4-dimethyl-2H,10H-[1,4]di-

oxepino[2,3-g]indole-10-carboxylate (63). To a stirred solution of

61 (5.30 g, 5.65 mmol, 1.0 equiv) under Ar in CH₂Cl₂(1.5 mL) at 0

°C were added Et₃N (0.79 mL, 5.65 mmol, 1.0 equiv) and DMAP (689.7

mg, 5.65 mmol, 1.0 equiv). After 5 min (BOC)₂O (3.70 g, 16.94 mmol,

3.0 equiv) was added in one portion. The reaction mixture was stirred

for 4.5 h and diluted with THF (40 mL). The remaining CH₂Cl₂was

removed under reduced pressure (until the reaction volume was 40 mL).

The flask was charged with n-Bu₄NF (17.0 mL, 17.0 mmol, 3.0 equiv,

1.0 M/THF), and the mixture was stirred at room temperature for ∼12

h. The solution was diluted with water and extracted with EtOAc.

[3r,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-[4-

[[(1,1-dimethylethyl)diphenylsilyl]oxy]-3-methyl-2-butenyl]-1-meth-

oxy-4-oxopyrrolo[1,2-a]pyrazin-3-yl]methyl]-3-[[(1,1-dimethylethyl)-

dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-2H,10H-

[1,4]dioxepino[2,3-g]indole-10-carboxylate (61). To a stirred solution

of 54 (8.47 g,10.13 mmol, 1.0 equiv) in CH₂Cl₂(101 mL) at 0 °C

under Ar was added Na₂CO₃(21.26 g, 202.6 mmol, 20.0 equiv). After

15 min Me₃OBF₄(7.49 g, 50.64 mmol, 5.0 equiv) was added in one

portion. The mixture was stirred for 5 min, the ice bath was removed,

and the reaction mixture was stirred for 4.5 h. The mixture was then

576 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

The organic layer was washed with brine, dried over Na₂SO₄, and

concentrated to dryness. The residue was purified by column chro-

matography (eluted with EtOAc) to yield 3.16 g (85%) of 63 as a white,

amorphous solid, mp 72-80 °C [The yield of 63 was 179 mg (98%)

with 260 mg of 61].

To a stirred solution of 64 (3.55 g, 5.76 mmol, 1.0 equiv) in CH₂Cl₂

(23 mL) at 0 °C under Ar was added 2,6-lutidine (0.74 mL, 6.34 mmol,

1.1 equiv) followed by tert-butyldimethylsilyl triflate (1.08 mL, 6.34

mmol, 1.1 equiv). After 3 h an additional amount (1.1 equiv) of each

reagent was added to the reaction flask; after stirring for 2 h, an

additional amount (1.1 equiv) of each reagent was added. The mixture

was stirred for 1 h, diluted with EtOAc, washed four times with water

and once with brine, dried over Na₂SO₄, and concentrated under reduced

pressure. The residue was purified by column chromatography (eluted

with 1:1 hexanes/EtOAc) to yield 3.23 g (77%) of 66 as an amorphous,

white solid. An analytical sample was obtained by PTLC on silica gel

(eluted with 1:1 hexanes/EtOAc).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.12 (6H, s), 0.13 (6H, s), 0.88 (18H, s), 1.06 (6H, s), 1.47 (6H, s),

1.59 (18H, s), 1.65 (6H, s), 1.78-1.98 (8H, s), 2.02-2.12 (2H, m),

2.86 (2H, dd, J ) 9.0, 14.6 Hz), 3.31-3.34 (2H, m), 3.33 (2H, dd, J

) 4.0, 13.6 Hz), 3.62 (3H, s), 3.64 (3H, s), 3.71-3.79 (2H, m), 3.73

(1H, dd, J ) 4.2, 9.8 Hz), 3.77 (1H, dd, J ) 4.4, 9.7 Hz), 3.92 (4H, s),

3.94-4.01 (4H, m), 4.15 (2H, dd, J ) 3.8, 12.4 Hz), 4.32-4.37 (2H,

m), 5.28-5.30 (2H, m), 6.87 (2H, d, J ) 8.3 Hz), 7.12 (1H, d, J ) 8.3

Hz), 7.13 (1H, d, J ) 8.3 Hz), 7.38 (2H, s). IR (NaCl, neat): 2930,

1750, 1691, 1652, 1494, 1424, 1366, 1248, 1159, 1088 cm^-1. Mass

spectrum (EI): m/e (relative intensity) 729 (M⁺, 4.2), 731 (M + 2,

2.1), 629 (9.4), 361 (24.1), 360 (100), 167 (94.8), 57.2 (63). Microanal.

Calcd for C₃₈H₅₆N₃O₇SiCl: C, 62.49; H, 7.73; N, 5.75. Found: C,

62.57; H, 7.71; N, 5.55.

[3r,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-(4-

chloro-3-methyl-2-butenyl)-1-methoxy-4-oxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-

4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate (67).

To a stirred solution of 65 (2.73 g, 4.43 mmol, 1.0 equiv) under Ar at

0 °C in CH₂Cl₂(18 mL) was added 2,6-lutidine (0.57 mL, 4.87 mmol,

1.1 equiv) followed by tert-butyldimethylsilyl triflate (0.87 mL, 4.87

mmol, 1.1 equiv). After 1 h, 1.1 equiv of each reagent was added and

stirred for 3 h. The solution was diluted with EtOAc, washed with

water and brine, dried over Na₂SO₄and concentrated under reduced

pressure. The residue was purified by column chromatography (eluted

with 1:2 EtOAc/hexanes) to yield 2.76 g (85%) of 67 as a white

amorphous solid. An analytical sample was obtained by PTLC on silica

gel (eluted with 1:2 EtOAc/hexanes).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.12 (6H, s), 0.13 (6H, s), 0.87 (18H, s), 1.05 (3H, s), 1.06 (3H, s),

1.47 (6H, s), 1.50-1.53 (2H, m), 1.58 (18H, s), 1.65 (6H, s), 1.72-

1.91 (6H, m), 2.21-2.37 (4H, m), 3.06-3.19 (2H, m), 3.28-3.36 (4H,

m), 3.56 (3H, s), 3.60 (3H, s), 3.63-3.87 (4H, m): 3.89 (4H, s), 3.93

(2H, dd, J ) 3.9, 9.8 Hz), 4.13-4.18 (2H, m), 4.22-4.35 (2H, m),

5.30-5.40 (2H, m), 6.85 (1H, d, J ) 8.3 Hz), 6.86 (1H, d, J ) 8.3

Hz), 7.19-7.26 (4H, m). IR (NaCl, neat): 2949, 1751, 1693, 1652,

1493, 1424, 1369, 1250, 1156, 1086 cm^-1. Microanal. Calcd for C₃₈-

H₅₆N₃O₇SiCl: C, 62.49; H, 7.73; N, 5.75. Found: C, 62.29; H, 7.61;

N, 5.76. HRMS (EI): 729.3555 (C₃₈H₅₆N₃O₇SiCl requires 729.3576).

1,1-Dimethylethyl 8-[[7,8-Dihydro-1-methoxy-10-(1-methylethe-

nyl)-4-oxo-6H-3,8a-ethanopyrrolo[1,2-a]pyrazin-3(4H)-yl]]methyl]-

3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-4,4-dimethyl-

2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate (68). To a stirred

solution of 66 (1.43 g, 1.96 mmol, 1.0 equiv) in benzene (300 mL)

was added NaH (939 mg, 39.16 mmol, 20.0 equiv, freshly washed in

pentane). This mixture was gently stirred at reflux temperature for

8.25 h, diluted with EtOAc, and washed with water and dilute HCl.

The organic layer was isolated, washed with brine, dried over Na₂SO₄,

and concentrated under reduced pressure. The residue was purified

by radial chromatography (eluted with 1:3 EtOAc/hexanes) to yield

1.26 g of 68 (93%). [The yield of 68 was 2.52 g (86%) from 3.10 g

of 66.]

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.16 (3H, s), 1.18 (3H, s), 1.51 (3H, s), 1.52 (3H, s), 1.55 (6H, s), 1.57

(18H, s), 1.60-2.14 (10H, m, 2H D₂O exch), 2.22-2.37 (4H, m), 3.06-

3.18 (3H, m, 1H D₂O exch), 3.26-3.36 (5H, m, 1H D₂O exch), 3.55

(3H, s), 3.56 (2H, br s), 3.60 (3H, s), 3.63-3.72 (2H, m), 3.89 (4H,

m), 4.18-4.23 (2H, m), 4.25 (4H, br s), 5.21-5.27 (2H, m), 6.857

(1H, d, J ) 8.3 Hz), 6.861 (1H, d, J ) 8.3 Hz), 7.22 (2H, d, J ) 8.3

Hz), 7.24 (2H, s). IR (NaCl, neat): 3401 (br), 2976, 1747, 1692, 1632,

1496, 1436, 1371, 1251, 1158, 733 cm^-1

(C₃₂H₄₃N₃O₈requires 597.3050).

. HRMS (EI): 597.3050

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-(4-

chloro-3-methyl-2-butenyl)-1-methoxy-4-oxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3,4-dihydro-3-hydroxy-4,4-dimethyl-2H,10H-[1,4]di-

oxepino[2,3-g]indole-10-carboxylate (64). Dimethyl sulfide (0.67 mL,

9.13 mmol, 8.0 equiv) was added dropwise to a stirred solution of NCS

(1.22 g, 9.13 mmol, 8.0 equiv) in CH₂Cl₂(51 mL) at 0 °C under Ar.

The resulting mixture was stirred for 10 min and then cooled to -23

°C. After 10 min, 62 (682.4 mg, 1.14 mmol, 1.0 equiv) was added to

the flask in one portion and stirring continued for 6 h. At this time

the reaction flask was placed in a freezer (-35 °C) for 16 h, followed

by an additional 10 h of stirring at -23 °C. The mixture was then

diluted with EtOAc, washed with water and brine, dried over Na₂SO₄,

and concentrated under reduced pressure. The residue was purified

by radial chromatography (eluted with 1:2 hexanes/EtOAc) to yield

565.8 mg (81%) of 64 as a white amorphous solid. [The yield of 64

was 2.12 g (37% or 74% based on recovered 62) with 5.60 g of 62.]

An analytical sample was obtained by PTLC on silica gel (eluted with

2:1 EtOAc/hexanes).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.17 (6H, s), 1.52 (6H, s), 1.57 (18H, s), 1.65 (6H, s), 1.73-2.20 (10H,

m), 2.84 (2H, dd, J ) 9.0, 14.4 Hz), 3.06 (1H, br s, D₂O exch), 3.10

(1H, br s, D₂O exch), 3.26-3.36 (4H, m), 3.55-3.58 (4H, m), 3.62

(3H, s), 3.63 (3H, s), 3.91 (4H, s), 3.95-4.05 (2H, m), 4.24-4.25 (4H,

m), 4.30-4.36 (2H, m), 5.28 (2H, m), 6.88 (2H, d, J ) 8.3 Hz), 7.14

(1H, d, J ) 8.3 Hz), 7.15 (1H, d, J ) 8.3 Hz), 7.376 (1H, s), 7.384

(1H, s). IR (NaCl, neat): 3403, 2979, 1750, 1716, 1642, 1348, 1154

cm^-1

. HRMS (EI): 615.2709 (C₃₂H₄₂N₃O₇Cl requires 615.2711).

Microanal. Calcd for C₃₂H₄₂N₃O₇Cl: C, 62.38; H, 6.87; N, 6.82.

Found: C, 62.53; H, 6.86; N, 6.67.

[3r,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-(4-

chloro-3-methyl-2-butenyl)-1-methoxy-4-oxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3,4-dihydro-3-hydroxy-4,4-dimethyl-2H,10H-[1,4]di-

oxepino[2,3-g]-indole-10-carboxylate (65). To a stirred solution of

NCS (5.67 g, 42.4 mmol, 8.0 equiv) at 0 °C under Ar in CH₂Cl₂(206

mL) was added dimethyl sulfide (3.12 mL, 42.4 mmol, 8.0 equiv)

dropwise. After 0.5 h the mixture was cooled (-23 °C) and stirred

for an additional 0.5 h. At this time the lactim ether-diol 63 (3.17 g,

5.30 mmol, 1.0 equiv) was added [approximately 3 g was added as a

solid; the remaining amount was added as a solution in CH₂Cl₂(30

mL) via cannula]. The white mixture was stirred for 12 h, diluted

with EtOAc, washed with water and brine, dried over Na₂SO₄, and

concentrated under reduced pressure. The residue was purified by flash

column chromatography (eluted with 2:1 hexanes/EtOAc; then 1:1

hexanes/EtOAc) to afford 2.80 g (86%) of 65 as a glass.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.17 (3H, s), 1.18 (3H, s), 1.52 (3H, s), 1.54 (3H, s), 1.57 (18H, s),

1.65 (6H, s), 1.71-1.92 (8H, m), 2.24-2.39 (4H, m), 3.03-3.19 (4H,

m, 2H D₂O exch), 3.28-3.37 (4H, m), 3.56 (3H, s), 3.60 (3H, s), 3.59-

3.75 (4H, m), 3.89 (4H, s), 4.21-4.29 (6H, m), 5.35 (2H, t, J ) 7.5

Hz), 6.86 (1H, d, J ) 8.3 Hz), 6.87 (1H, d, J ) 8.3 Hz), 7.23 (2H, d,

J ) 8.3 Hz), 7.22 (1H, s), 7.27 (1H, s). IR (NaCl, neat): 3412 (br),

To a stirred solution of 67 (1.60 g, 2.19 mmol, 1.0 equiv) in benzene

(313 mL) was added NaH (1.05 g, 43.8 mmol, 20.0 equiv, freshly

washed in pentane). This mixture was gently stirred at reflux

temperature for 5.5 h and stirred at room temperature overnight. At

this time, a small sample was removed, washed with water, and

extracted with EtOAc. A crude proton NMR (in CDCl₃) indicated that

the reaction was complete. The remaining mixture was diluted with

EtOAc and washed with water. The organic layer was washed with

2976, 1752, 1698, 1638, 1365, 1251, 1158 cm^-1

615.2714 (C₃₂H₄₂N₃O₇Cl requires 615.2711).

. HRMS (EI):

[3â,8aâ(E)]-1,1-Dimethylethyl 8-[[3,4,6,7,8,8a-Hexahydro-8a-(4-

chloro-3-methyl-2-butenyl)-1-methoxy-4-oxopyrrolo[1,2-a]pyrazin-

3-yl]methyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-

4,4-dimethyl-2H,10H-[1,4]dioxepino[2,3-g]indole-10-carboxylate (66).

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 577

brine, dried over Na₂SO₄, and concentrated under reduced pressure.

The two samples were combined and purified by radial chromatography

(eluted with 1:3 EtOAc/hexanes) to yield 1.29 g of 68 (85%). An

analytical sample was obtained by PTLC on silica gel (eluted with 1:3

EtOAc/hexanes); the product was obtained as a white solid, mp 105-

108 °C.

(eluted with 1:2 hexanes/EtOAc) to afford 19.6 mg (74%) of 71 as a

white amorphous solid.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

TMS 0.10-0.15 (12H, m), 0.89 (9H, s), 0.90 (9H, s), 1.09 (6H, s),

1.26 (3H, s), 1.29 (3H, s), 1.33 (3H, s), 1.36 (3H, s), 1.46 (3H, s), 1.48

(3H, s), 1.58 (9H, s), 1.60 (9H, s), 1.76-2.51 (10H, m), 2.23-2.31

(2H, m), 2.60-2.70 (2H, m), 3.027 (1H, ¹/₂ABq, J ) 16.4 Hz), 3.032

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.12 (6H, s), 0.13 (6H, s), 0.872 (9H, s), 0.875 (9H, s), 1.06 (3H, s),

1.07 (3H, s), 1.46 (6H, s), 1.58 (18H, s), 1.61 (3H, s), 1.64 (3H, s),

1.72-2.03 (8H, m), 2.25-2.42 (2H, m), 2.47 (2H, dd, J ) 5.1, 9.7

Hz), 2.54 (2H, dd, J ) 5.8, 9.7 Hz), 3.05 (1H, ¹/₂ABq, J ) 15.0 Hz),

1

(1H, /₂ABq, J ) 16.4 Hz), 3.31-3.41 (2H, m), 3.46-3.54 (2H, m),

3.68 (2H, dd, J ) 9.1, 12.1 Hz), 3.77 (6H, s), 3.87-3.94 (2H, m),

3.90 (2H, ¹/₂ABq, J ) 16.3 Hz), 4.08 (2H, dd, J ) 3.5, 11.9 Hz), 6.79

(1H, d, J ) 8.3 Hz), 6.80 (1H, d, J ) 8.3 Hz), 7.063 (1H, d, J ) 8.3

Hz), 7.061 (1H, d, J ) 8.3 Hz). IR (NaCl, neat): 2952, 2886, 1745,

1683, 1640, 1496, 1412, 1355, 1252, 1232, 1156, 1140, 1111, 1090,

1052, 992, 838, 770 cm^-1. HRMS (EI): m/e 693.3810 (C₃₈H₅₅N₃O₇Si

requires 693.3810).

1

3.07 (1H, /₂ABq, J ) 15.0 Hz), 3.31-3.53 (6H, m), 3.57 (3H, s),

3.64 (3H, s), 3.73-3.89 (2H, m), 3.94 (2H, dd, J ) 3.7, 9.7 Hz), 4.17

(2H, dd, J ) 3.1, 11.6 Hz), 4.62 (1H, s), 4.75 (1H, s), 4.78 (1H, s),

4.85 (1H, s), 6.82 (2H, d, J ) 8.4 Hz), 7.31 (1H, d, J ) 8.4 Hz), 7.38

(1H, d, J ) 8.4 Hz), 7.44 (1H, s), 7.52 (1H, s). IR (NaCl, neat): 2935,

1752, 1684, 1637, 1496, 1418, 1365, 1350, 1250, 1220, 1156, 1083

cm^-1. HRMS (EI): m/e 693.3834 (C₃₈H₅₅N₃O₇Si requires 693.3809).

Microanal. Calcd for C₃₈H₅₅N₃O₇Si: C, 65.77; H, 7.99; N, 6.05.

Found: C, 65.85; H, 7.99; N, 5.91.

3-(Hydroxy)-3,4,8,12,13,14,14a,15-octahydro-4,4,15,15-tetramethyl-

9,17-dioxo-11H,16H-8a,13a-(iminomethano)-2H,9H-[1,4]dioxepino-

[2,3-a]indolizino[6,7-h]carbazole (76). To a stirred solution of 69 (150

mg, 0.22 mmol, 1.0 equiv) in CH₂Cl₂(4.4 mL) under N₂at 0 °C was

added TFA (1.4 mL, 17.8 mmol, 80 equiv) dropwise. The reaction

mixture was allowed to reach room temperature overnight. The solution

was concentrated and the residue taken up in EtOAc. The resulting

solution was washed with 10% Na₂CO₃and brine. The organic layer

was dried over Na₂SO₄and concentrated to dryness under reduced

pressure. The residue was purified by radial chromatography (eluted

with EtOAc) to yield 102 mg (95%) of 76. An analytical sample was

obtained by PTLC on silica gel (eluted with 1:1 EtOAc/hexanes) as a

white amorphous solid.

1,1-Dimethylethyl 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3,4,8,-

12,13,14,14a,15-octahydro-4,4,15,15-tetramethyl-9,17-dioxo-

11H,16H-8a,13a-(iminomethano)-2H,9H-[1,4]dioxepino[2,3-a]in-

dolizino[6,7-h] carbazole-16-carboxylate (69). To a flask charged

with PdCl₂(827.9 mg, 4.67 mmol, 3.0 equiv) and AgBF₄(605.3 mg,

3.11 mmol, 2.0 equiv) was added dry CH₃CN (50 mL). The mixture

was stirred for 6.5 h, when a solution of 68 (1.08 g, 1.56 mmol, 1.0

equiv) in CH₃CN (5.0 mL) was syringed into the flask. The reaction

mixture was stirred for 48 h, and EtOH (55 mL) was added, followed

by small portions of NaBH₄(590 mg, 15.6 mmol, 10.0 equiv) at 0 °C.

The addition was complete in 0.5 h, and the mixture was stirred for an

additional 0.5 h. The black mixture was filtered to remove palladium

and the solvent evaporated under reduced pressure. The residue was

dissolved in EtOAc, washed with dilute aqueous HCl (0.01 M) and

brine, dried over Na₂SO₄, and concentrated under reduced pressure.

The residue was purified by radial chromatography (eluted with 25:

25:1 CH₂Cl₂/Et₂O/MeOH) to afford 676.3 mg (63%) of 69 as a white

amorphous solid. An analytical sample was obtained by PTLC on silica

gel (eluted with 25:25:1 CH₂Cl₂/Et₂O/MeOH).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.081 (6H, s), 0.11 (6H, s), 0.87 (9H, s), 0.88 (9H, s), 1.08 (3H, s),

1.17 (3H, s), 1.26 (3H, s), 1.27 (3H, s), 1.34 (3H, s), 1.35 (3H, s), 1.44

(3H, s), 1.46 (3H, s), 1.56 (9H, s), 1.58 (9H, s), 1.81-1.90 (2H, m),

1.96-2.06 (6H, m), 2.20 (2H, dd, J ) 10.3, 13.5 Hz), 2.52-2.60 (4H,

m), 2.78 (2H, dt, J ) 6.5, 12.9 Hz), 3.36-3.49 (2H, m), 3.51-3.57

(2H, m), 3.63-3.84 (4H, m), 3.88-3.92 (2H, m), 4.04-4.16 (2H, m),

6.24 (1H, s, D₂O exch), 6.26 (1H, s, D₂O exch), 6.78 (1H, d, J ) 8.3

Hz), 6.80 (1H, d, J ) 8.5 Hz), 6.98 (1H, d, J ) 8.2 Hz), 6.99 (1H, d,

J ) 8.4 Hz). ¹³C NMR (75.5 MHz) (CDCl₃) (mixture of two

diastereomers): δ -5.2, -5.1, -5.0, -4.5, -4.3, 17.6. 18.7, 19.3,

19.7, 19.9, 24.3,.25.5, 25.6, 26.9, 26.2, 27.2, 27.8, 27.9, 28.3, 28.5,

29.1, 31.1, 36.2, 43.8, 50.5, 50.6, 53.3, 54.8, 55.7, 59.4, 60.2, 60.2,

66.3, 67.6, 71.1, 72.7, 75.9, 78.0, 80.5, 84.1, 84.3, 108.3, 112.4, 112.5,

113.6, 117.9, 118.5, 124.6, 124.9, 128.7, 128.9, 129.4, 137.7, 138.3,

139.4, 139.6, 143.0, 143.2, 152.9, 153.0, 168.3, 174.1. IR (neat): 3214,

2928, 2856, 1745, 1556, 1496, 1443, 1368, 1252, 1233, 1154, 1141,

1091, 1052, 994, 859, 838, 777, 733. Microanal. Calcd for C₃₇H₅₃N₃O₇-

Si: C, 65.36; H, 7.86; N, 6.18. Found: C, 65.18; H, 7.77; N, 6.18.

MS (EI): m/e (relative intensity) 679 (M⁺, 0.3), 580 (20.4), 579 (51),

73 (100). HRMS (EI): m/e 679.3661 (C₃₇H₅₃N₃O₇Si requires 679.3653).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.06 (3H, s), 1.08 (3H, s), 1.18 (3H, s), 1.20 (3H, s), 1.23 (3H, s), 1.29

(3H, s), 1.49 (3H, s), 1.55 (3H, s), 1.79-2.04 (8H, m), 2.17 (2H, td, J

) 5.1, 11.9 Hz), 2.43 (1H, m), 2.43 (1H, ¹/₂ABq, J ) 15.5 Hz), 2.51

(1H, dd, J ) 4.8, 10.2 Hz), 2.59 (1H, ¹/₂ABq, J ) 15.5 Hz), 2.78 (2H,

dt, J ) 6.5, 12.9 Hz), 3.21 (1H, br s, D₂O exch), 3.33-3.41 (3H, m),

3.41-3.56 (3H, m), 3.60 (1H, br s, D₂O exch), 3.70 (1H, ¹/₂ABq, J )

15.4 Hz), 3.78 (1H, ¹/₂ABq, J ) 15.4 Hz), 4.12 (2H, dd, J ) 8.4, 12.0

Hz), 4.25 (2H, td, J ) 4.0, 12.2 Hz), 6.65 (2H, s, D₂O exch), 6.72

(1H, d, J ) 8.3 Hz), 6.73 (1H, d, J ) 8.3 Hz), 7.02 (1H, d, J ) 7.9

Hz), 7.05 (1H, d, J ) 8.1 Hz), 7.98 (1H, s, D₂O exch), 8.10 (1H, s,

D₂O exch). IR (NaCl, neat): 3308, 1684, 1679, 1402, 1367, 1232,

1044, 733 cm^-1

465.2264).

. HRMS (EI): m/e 465.2248 (C₂₆H₃₁N₃O₅requires

14-Deoxy-29-demethyl-24,25-dihydro-25-hydroxy-12-oxo-17-nor-

paraherquamide (79). To a stirred mixture of 76 (16.5 mg, 0.035

mmol, 1.0 equiv) in CH₂Cl₂(0.7 mL) at 0 °C under N₂was added

Et₃N (4.6 µL, 0.04 mmol, 1.1 equiv) followed by t-BuOCl (5.4 µL,

0.04 mmol, 1.1 equiv). After 0.5 h, the resulting clear, yellow solution

was concentrated to dryness (the flask being kept cold). The residue

was immediately subjected to a solution of MeOH/H₂O/AcOH (40:20:

1) and stirred under N₂at room temperature for 0.5 h. The solution

was diluted with saturated NaHCO₃, and the organic layer was washed

three times with saturated NaHCO₃, washed with brine, dried over Na₂-

SO₄, and concentrated to dryness under reduced pressure. The residue

was purified by PTLC on silica gel (eluted with 20:1 CH₂Cl₂/MeOH)

to yield 5.0 mg (29%) of 79 as an amorphous solid.

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.46 (3H, s), 0.48 (3H, s), 0.93 (6H, s), 1.22 (3H, s), 1.23 (3H, s), 1.45

(3H, s), 1.51 (3H, s), 1.65-2.09 (14H, m), 2.71-2.79 (2H, m), 2.87

(2H, td, J ) 3.2, 9.3 Hz), 3.40-4.99 (2H, m), 3.56-3.66 (6H, m, 2H

D₂O exch), 4.08-4.26 (4H, m), 6.56 (1H, d, J ) 8.1 Hz), 6.61 (1H, d,

J ) 8.1 Hz), 6.80 (1H, d, J ) 7.7 Hz), 6.82 (1H, d, J ) 7.8 Hz), 6.96

1,1-Dimethylethyl 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3,4,8,-

12,13,14,14a,15-octahydro-4,4,15,15-tetramethyl-17-methoxy-9-oxo-

11H,16H-8a,13a-(iminomethano)-2H,9H-[1,4]dioxepino[2,3-a]in-

dolizino[6,7-h]carbazole-16-carboxylate (71). To a stirred solution

of 69 (26.1 mg, 0.38 mmol, 1.0 equiv) in CH₂Cl₂(1 mL) under Ar at

0 °C was added Na₂CO₃(81.0 mg, 0.76 mmol, 20.0 equiv). After 10

min Me₃OBF₄(28.3 mg, 0.191 mmol, 5.0 equiv) was added in one

portion. The mixture was stirred for 4 h at room temperature, poured

into water, and extracted with EtOAc. The organic layer was washed

with brine, dried over Na₂SO₄, and concentrated to dryness under

reduced pressure. The residue was purified by PTLC on silica gel

(1H, s, D₂O exch), 7.09 (1H, s, D₂O exch), 8.03 (1H, s, D₂O exch),

8.11 (1H, s, D₂O exch). IR (NaCl, neat): 3411, 3237, 1698, 1632,

1496, 1404, 1333, 1213, 728 cm^-1. Mass spectrum (EI): m/e (relative

intensity) 481 (M⁺, 23.9), 412 (15.2), 249 (12.7), 220 (100), 149 (60.6).

HRMS (EI): m/e 481.2194 (C₂₆H₃₁N₃O₆requires 481.2213).

1,1-Dimethylethyl 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3,4,8,-

12,13,14,14a,15-octahydro-4,4,15,15-tetramethyl-17-oxo-11H,16H-

8a,13a-(iminomethano)-2H,9H-[1,4]dioxepino[2,3-a]indolizino[6,7-

h]carbazole-16-carboxylate (70). To a stirred solution of 69 (164

mg, 0.24 mmol, 1.0 equiv) in THF (4.9 mL) at -78 °C under Ar was

added Et₃Al (0.14 mL, 0.26 mmol, 1.1 equiv, 1.9 M in toluene)

578 J. Am. Chem. Soc., Vol. 118, No. 3, 1996

Cushing et al.

dropwise. After 10 min the solution was warmed to 0 °C and AlH₃‚-

DMEA (6.0 mL, 1.20 mmol, 5.0 equiv, 0.2 M in toluene) was added

dropwise. The ice bath was removed and the solution stirred for 1 h

and 20 min at room temperature. At this time MeOH (4.7 mL) and

AcOH (0.31 mL) were syringed into the flask, followed by NaCNBH₃

(179 mg, 2.85 mmol, 11.9 equiv). This mixture was stirred for 10

min, and the solvent was removed under reduced pressure and replaced

with ethyl acetate. The resulting solution was washed with NaHCO₃

(saturated) and brine, dried over Na₂SO₄, and concentrated under

reduced pressure. The residue was purified by radial chromatography

(eluted with 1:1 hexanes/EtOAc) to yield 102 mg (65%) of 70 as a

white amorphous solid. An analytical sample was obtained by PTLC

on silica gel (eluted with 1:1 EtOAc/hexanes).

(3H, s), 1.54 (6H, s), 1.88-2.00 (10H, m), 2.07-2.22 (6H, m), 2.63-

1

2.72 (2H, m), 2.79 (1H, /₂ABq, J ) 15.1 Hz), 2.80 (1H, /₂ABq, J

) 15.1 Hz), 3.01-3.07 (4H, m, 2H D₂O exch), 3.07 (6H, s), 3.17 (1H,

1

¹/₂ABq, J ) 15.1 Hz), 3.19 (1H, /₂ABq, J ) 15.4 Hz), 3.37-3.43

(2H, m), 3.62 (2H, br s), 4.20 (2H, dd, J ) 4.4, 12.3 Hz), 4.29 (1H,

dd, J ) 4.0, 12.3 Hz), 4.31 (1H, dd, J ) 4.0, 12.3 Hz), 6.750 (1H, d,

J ) 8.4 Hz), 6.753 (1H, d, J ) 8.3 Hz), 7.01 (2H, d, J ) 8.4 Hz), 8.01

(2H, s, D₂O exch). ¹³C NMR (75.5 MHz) (CDCl₃) (mixture of two

diastereomers): δ 14.0, 20.8, 22.6, 23.9, 24.4, 24.5, 24.7, 25.1, 27.7,

27.9, 30.2, 30.3, 31.3, 34.4, 45.9, 54.3, 57.4, 60.0, 60.2, 64.0, 71.0,

75.5, 76.6, 77.0, 77.4, 79.5, 104.6, 112.2, 116.17, 116.22, 125.0, 129.2,

137.2, 140.4, 141.6, 171.0, 174.3. IR (NaCl, neat): 3324, 2954, 1654,

1507, 1474, 1365, 1235, 1071, 1049, 908, 733 cm^-1. Microanal. Calcd

for C₂₇H₃₅N₃O₄Si: C, 69.65; H, 7.58; N, 9.02. Found: C, 69.54; H,

7.66; N, 8.89. Mass spectrum (EI): m/e (relative intensity) 465 (M⁺,

9.7), 406 (14.5), 287 (11.8), 178 (100). HRMS (EI): m/e 465.2625

(C₂₇H₃₅N₃O₄Si requires 465.2628).

14-Deoxy-24,25-dihydro-25-hydroxy-17-norparaherquamide (80).

To a stirred solution of 73 (99 mg, 0.21 mmol, 1.0 equiv) in pyridine

(4 mL) at -15 °C under Ar was added t-BuOCl (37 µL, 0.32 mmol,

1.5 equiv). After 2 h the solvent was removed under reduced pressure

to give 106 mg (quantitative) of the crude chloroindolenines (74/75 as

a mixture of epimers). The majority of the crude chloroindolenines,

74/75 (71 mg, 0.14 mmol, 1.0 equiv), was dissolved in THF (10 mL)

and water (1 mL), and p-toluenesulfonic acid monohydrate (135 mg,

0.41 mmol, 15 equiv) was added. The resulting yellow solution was

stirred at reflux temperature for 20 min and diluted with EtOAc and

aqueous K₂CO₃. The organic layer was isolated, washed with brine,

dried over Na₂SO₄, and concentrated to dryness under reduced pressure.

The residue was purified by PTLC on silica gel (eluted with 20:1 CH₂-

Cl₂/MeOH) to yield (from the chloroindolenines) 52 mg (76%) of 80

and 2.7 mg (4%) of 81.

¹H NMR (300 MHz) (CDCl₃) (80 mixture of two diastereomers): δ

TMS 0.80 (3H, s), 0.83 (3H, s), 1.08 (3H, s), 1.10 (3H, s), 1.22 (3H,

s), 1.26 (3H, s), 1.50 (3H, s): 1.52 (3H, s), 1.40-1.60 (8H, m), 1.77-

1.93 (8H, m), 2.05-2.21 (2H, m), 2.55-2.71 (4H, m), 3.02-3.10 (4H,

m), 3.06 (6H, s), 3.63 (4H, br s, 2H D₂O exch), 4.05-4.24 (4H, m),

6.60 (1H, d, J ) 8.1 Hz), 6.62 (1H, d, J ) 8.2 Hz), 6.78 (1H, d, J )

8.1 Hz), 6.79 (1H, d, J ) 8.2 Hz), 7.42 (1H, s, D₂O exch), 7.45 (1H,

s, D₂O exch). IR (NaCl, neat): 3333, 2974, 2933, 1703, 1651, 1646,

1631, 1456, 1395, 1323, 1200, 1046, 903, 728 cm^-1. Mass spectrum

(EI): m/e (relative intensity) 481 (M⁺, 0.7), 422 (20.7), 421 (15), 135

(48), 133 (100). HRMS (CI): m/e 481 (C₂₇H₃₅N₃O₅requires 481.2578),

[M + H] 482.2645 (C₂₇H₃₆N₃O₅requires 482.2655).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.085 (6H, s), 0.11 (6H, s), 0.87 (9H, s), 0.88 (9H, s), 1.12 (3H, s),

1.15 (3H, s), 1.23 (3H, s), 1.24 (3H, s), 1.36 (3H, s), 1.37 (3H, s), 1.45

(6H, s), 1.59 (9H, s), 1.61 (9H, s), 1.88-1.92 (6H, s), 1.97-2.10 (2H,

1

m), 2.17-2.26 (2H, m), 2.54-2.63 (2H, m), 2.70 (2H, /₂ABq, J )

1

15.5 Hz), 2.829 (1H, /₂ABq, J )15.4 Hz), 2.835 (1H, /₂ABq, J )

15.6 Hz), 3.06-3.09 (2H, m), 3.45-3.49 (4H, m), 3.67-3.85 (4H, m),

3.90 (2H, dd, J ) 3.4, 8.7 Hz), 4.09-4.18 (4H, m), 6.03 (2H, s, D₂O

exch), 6.78 (1H, d, J ) 8.3 Hz), 6.79 (1H, d, J ) 8.3 Hz), 6.89 (2H,

d, J ) 8.3 Hz). IR (NaCl, neat): 3227, 2928, 1746, 1683, 1597, 1371,

1254, 1233, 1154, 1138, 1090, 836 cm^-1. Mass spectrum (EI): m/e

(relative intensity) 665 (M⁺, 0.3), 565 (30.6), 521 (40.1), 164 (100).

Microanal. Calcd for C₃₇H₅₅N₃O₆Si: C, 66.73; H, 8.32; N, 6.31.

Found: C, 66.50; H, 8.18; N, 6.33. HRMS (EI): m/e 665.38365

(C₃₇H₅₅N₃O₆Si requires 665.3860).

1,1-Dimethylethyl 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3,4,8,-

12,13,14,14a,15-octahydro-4,4,15,15,18-pentamethyl-17-oxo-11H,-

16H-8a,13a-(iminomethano)-2H,9H-[1,4]dioxepino[2,3-a]indolizino-

[6,7-h]carbazole-16-carboxylate (72). To a stirred solution of 70

(147.5 mg, 0.22 mmol, 1.0 equiv) in DMF (2.2 mL) under Ar at 0 °C

was added NaH (13.3 mg, 0.55 mmol, 2.5 equiv). After 5 min, MeI

(27.6 µL, 0.44 mmol, 2.0 equiv) was syringed in dropwise. The mixture

was stirred for 4 h, when a small amount of water and mercaptoethanol

(21.6 µL) were added. After a few minutes, the mixture was diluted

with water and extracted with 1:1 hexanes/EtOAc. The organic layer

was washed with brine, dried over Na₂SO₄, and concentrated under

reduced pressure. The residue was purified by radial chromatography

(eluted with 1:2 hexanes/EtOAc) to yield 146.9 mg (98%) of 72 as a

white amorphous solid. An analytical sample was obtained by PTLC

on silica gel (eluted with 1:1 EtOAc/hexanes).

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

0.089 (6H, s), 0.11 (6H, s), 0.87 (9H, s), 0.88 (9H, s), 1.13 (3H, s),

1.15 (3H, s), 1.25 (6H, s), 1.36 (3H, s), 1.37 (3H, s), 1.46 (6H, s), 1.59

(9H, s), 1.61 (9H, s), 1.86-2.06 (10H, m), 2.09-2.20 (6H, m), 2.61-

¹H NMR (500 MHz) (CDCl₃) (81 mixture of two diastereomers): δ

TMS 0.53 (3H, s), 0.56 (3H, s), 0.84 (3H, s), 0.86 (3H, s), 1.22 (3H,

s), 1.25 (3H, s), 1.50 (3H, s), 1.52 (3H, s), 1.41-1.73 (8H, m), 1.83-

1.90 (8H, m), 2.09-2.13 (2H, m), 2.28-2.41 (6H, m), 2.51-2.58 (2H,

m), 3.00 (3H, s), 3.01 (3H, s), 3.63 (2H, br s), 3.78 (1H, D₂O exch),

3.81 (1H, s D₂O exch), 4.05-4.24 (4H, m), 6.60 (2H, d, J ) 8.0 Hz),

6.62 (2H, d, J ) 7.4 Hz), 7.42 (2H, s, D₂O exch). IR (NaCl, neat):

3271, 2924, 2854, 1714, 1644, 1496, 1464, 1393, 1375, 1211, 1142,

1

2.70 (2H, m), 2.747 (1H, /₂ABq, J ) 15.4 Hz), 2.754 (1H, /₂ABq,

1

J ) 15.4 Hz), 2.30-3.05 (2H, m), 3.05 (6H, s), 3.14 (2H, /₂ABq, J

) 15.4 Hz), 3.39 (2H, d, J ) 10.5 Hz), 3.74-3.85 (2H, m), 3.89-

3.93 (2H, m), 4.07-4.18 (2H, m), 6.797 (1H, d, J ) 8.3 Hz), 6.804

(1H, d, J ) 8.3 Hz), 6.93 (2H, d, J ) 8.3 Hz). IR (NaCl, neat): 2921,

1747, 1665, 1496, 1371, 1251, 1235, 1158, 1142, 1108, 1093, 837,

755 cm^-1. Mass spectrum (EI): m/e (relative intensity) 679 (M⁺, 2.1),

579 (4.2), 520 (4.2), 178 (100). Microanal. Calcd for C₃₈H₅₇N₃O₆Si:

C, 67.12; H, 8.45; N, 6.18. Found: C, 67.33; H, 8.27; N, 6.44. HRMS

(EI): m/e 679.4008 (C₃₈H₅₇N₃O₆Si requires 679.4017).

1066 cm^-1

.

(+)-Paraherquamide B (12). To a stirred solution of 80 (22.5 mg,

0.047 mmol, 1.0 equiv) in DMPU (500 µL) under Ar at room

temperature was added MTPI (90 mg, 0.20 mmol, 4.0 equiv). After

16 h KOH (10 mL, 1 M) was added, and the mixture was stirred for

an additional 10 min. The pH was adjusted to 2 (addition of HCl) and

the mixture extracted with EtOAc. The mixture was diluted with 1:1

hexanes/EtOAc and washed with water and brine. The organic layer

was dried over Na₂SO₄and concentrated under reduced pressure. The

residue was purified by PTLC on silica gel (eluted with 20:1 CH₂Cl₂/

MeOH) to afford 17.1 mg (79%) of (+)-paraherquamide B (12) as a

white, amorphous solid. This material proved to be identical to an

3-Hydroxy-3,4,8,12,13,14,14a,15-octahydro-4,4,15,15,18-penta-

methyl-17-oxo-11H,16H-8a,13a-(iminomethano)-2H,9H-[1,4]diox-

epino[2,3-a]indolizino[6,7-h]carbazole (73). To a stirred solution of

72 (294.7 mg, 0.43 mmol, 1.0 equiv) in CH₂Cl₂(8.7 mL) at 0 °C under

Ar was added TFA (2.77 mL, 34.7 mmol, 80.0 equiv) dropwise. The

solution was stirred for 15 h, the temperature being maintained at 15

°C. At this time the solution was concentrated under reduced pressure,

diluted with EtOAc, washed with saturated NaHCO₃and brine, dried

over Na₂SO₄, and concentrated under reduced pressure. The residue

was purified by radial chromatography (eluted with EtOAc) to yield

194.8 mg (96%) of 73 as a white amorphous solid. An analytical

sample was obtained by PTLC on silica gel (eluted with 1:1 EtOAc/

hexanes).

1

authentic sample of natural (-)-paraherquamide B by H NMR, ¹³C

NMR, TLC mobility, IR, mass spectrum, and UV (see text for CD

spectrum, Figure 7).

¹H NMR (300 MHz) (CDCl₃): δ TMS 0.82 (3H, s), 1.09 (3H, s),

1.40 (3H, s), 1.41 (3H, s), 1.64 (1H, dd, J ) 9.7, 12.4 Hz), 1.73-1.92

(4H, m), 1.82 (1H, ¹/₂ABq, J ) 15.5 Hz), 2.16 (1H, dd, J ) 8.6, 17.8

¹H NMR (300 MHz) (CDCl₃) (mixture of two diastereomers): δ

1.21 (3H, s), 1.23 (3H, s), 1.29 (3H, s), 1.32 (3H, s), 1.42 (3H, s), 1.45

Hz), 2.54-2.59 (1H, m), 2.61 (1H, /₂ABq, J ) 11.1 Hz), 2.66 (1H,

1

¹/₂ABq, J ) 15.5 Hz), 3.03-3.10 (2H, m), 3.05 (3H, s), 3.60 (1H, ¹/₂

Stereocontrolled Total Synthesis of (+)-Paraherquamide B

J. Am. Chem. Soc., Vol. 118, No. 3, 1996 579

ABq, J ) 11.1 Hz), 4.87 (1H, d, J ) 7.7 Hz), 6.30 (1H, d, J ) 7.7

Hz), 6.64 (1H, d, J ) 8.2 Hz), 6.78 (1H, d, J ) 8.2 Hz), 8.5 (1H, br

s, D₂O exch). ¹³C NMR (75.5 MHz) (CDCl₃): δ 20.7 (q), 23.8 (q),

26.2 (q), 28.2 (q), 28.8 (t), 29.8 (t), 29.9 (q), 37.2 (t), 46.1 (s), 52.8

(d), 53.8 (t), 59.5 (t), 63.0 (s), 65.2 (s), 67.4 (s), 79.7 (s), 115.0 (d),

117.2 (d), 120.3 (d), 125.3 (s), 132.5 (s), 135.3 (s), 139.0 (d), 146.0

(s), 172.9 (s), 183.1 (s). IR (NaCl, neat): 3190, 2974, 2933, 1703,

1697, 1651, 1631, 1503, 1456, 1328, 1195, 1046 728 cm^-1. UV: λ_max

226 nm (ꢀ ) 30 200). [R]²⁵_D) (+0.4/7.75 × 10^-3)° ) +51.6° (CHCl₃,

c ) 0.008). Mass spectrum (EI): m/e (relative intensity) 463 (M⁺,

0.5), 404 (15.6), 135 (41.5), 133 (100). HRMS (EI): m/e 463.2456

(C₂₇H₃₃N₃O₄requires 463.2471).

28.3 (q), 29.0 (t), 29.7 (d), 35.6 (t), 36.7 (t), 48.0 (t), 52.4 (d), 66.7 (s),

71.0 (t), 75.8 (d), 76.6 (s), 79.8 (d), 80.4 (s), 83.1 (s), 113.6 (d), 113.8

(t), 114.7 (s), 120.0 (d), 126.1 (d), 127.8 (s), 129.3 (s), 140.4 (s), 141.7

(s), 146.4 (s), 148.6 (s), 155.0 (s), 169.8 (s), 175.7 (s). IR (neat): 2926,

1783, 1754, 1715, 1652, 1494, 1457, 1367, 1250, 1160, 1087 cm^-1

.

Acknowledgment. This work was supported in part by the

National Institutes of Health (Grant CA 43969) and the National

Science Foundation (CHE 9320010). Acknowledgment is made

to the donors of the Petroleum Research Fund, administered

by the American Chemical Society, and The Colorado State

University Agricultural Experiment Station (USDA SAES

Western Project W-122) for partial support of this work. Mass

spectra were obtained on instruments supported by the National

Institutes of Health Shared Instrumentation Grant GM49631.

We would like to thank Dr. Chris Rithner of Colorado State

University for technical assistance with several 2D NMR

experiments. Narashima Sreerama and Prof. Robert W. Woody

(Department of Biochemistry and Molecular Biology, Colorado

State University) are gratefully acknowledged for help in

obtaining CD spectra. We would also like to acknowledge Dr.

Dusan Stanojevic and Prof. Gregory L. Verdine (Department

of Chemistry, Harvard University) for their assistance in

obtaining CD spectra of paraherquamide B. We are grateful

to Dr. John Ondeyka of Merck & Co. for furnishing NMR

spectra of natural paraherquamide B. J.F.S.-C. thanks the

Conselleria de Educacio i Ciencia de la Generalitat Valenciana

(Spain) for a fellowship. We also wish to acknowledge Renee

Gallegos (Colorado State University), Felix Sancenon (Univer-

sity of Valencia), and M. Eugenia Martinez (University of

Valencia) for valuable assistance in isolating natural (-)-

paraherquamide B from P. fellutanum. Mr. Dan Bond is

gratefully acknowledged for providing synthetic chemical

technical assistance.

Spiro Product 56. ¹H NMR (300 MHz) (acetone-d₆) (mixture of

two diastereomers): δ TMS 0.21 (12H, s), 0.93 (18H, s), 1.13 (6H, s),

1.41 (18H, s), 1.48 (6H, s), 1.62 (18H, s), 1.82 (6H, s), 1.88-2.15

(6H, m), 2.54 (2H, t, J ) 11.3 Hz), 2.81-2.83 (4H, m), 3.02-3.06

(4H, m), 3.36-3.42 (2H, m), 3.62-3.64 (2H, m), 3.88 (2H, dd, J )

9.3, 12.2 Hz), 3.99 (2H, dd, J ) 3.5, 9.3 Hz), 4.21 (2H, dd, J ) 3.5,

12.2 Hz), 4.61-4.83 (4H, m), 4.96 (2H, br s), 5.07 (2H, br s), 5.94

(2H, d, J ) 8.5 Hz, D₂O exch), 6.92 (2H, d, J ) 8.3 Hz), 7.25 (2H, d,

J ) 8.3 Hz), 7.41 (2H, s). ¹³C NMR (75.5 MHz) (CDCl₃) (mixture of

two diastereomers): δ -4.9 (q), -4.0 (q), 16.5 (q), 17.9 (s), 18.4 (q),

24.1 (t), 25.7 (q), 28.0 (q), 28.3 (q), 28.6 (q), 29.4 (t), 29.7 (d), 35.6

(t), 36.6 (t), 47.9 (t), 51.7 (d), 66.6 (s), 70.9 (t), 75.9 (d), 76.6 (s), 79.8

(d), 80.4 (s), 83.1 (s), 113.7 (d), 113.9 (t), 114.6 (s), 120.3 (d), 126.4

(d), 127.9 (s), 129.3 (s), 140.4 (s), 141.8 (s), 146.6 (s), 148.5 (s), 155.0

(s), 169.7 (s), 176.6 (s). IR (NaCl, neat): 2932, 1780, 1752, 1714,

1649, 1496, 1425, 1365, 1251, 1229, 1158, 1088 cm^-1

.

Spiro Product 57. ¹H NMR (300 MHz) (acetone-d₆) (mixture of

two diastereomers): δ TMS 0.21 (12H, s), 0.94 (18H, s), 1.14 (6H, s),

1.41 (18H, s), 1.47 (6H, s), 1.62 (18H, s), 1.80 (6H, s), 1.96-2.07

(6H, m), 2.58 (2H, t, J ) 11.3 Hz), 2.84 (4H, br s), 2.98-3.13 (4H,

m), 3.48-3.50 (2H, m), 3.51-3.52 (2H, m), 3.88 (2H, dd, J ) 9.3,

12.1 Hz), 4.00 (2H, dd, J ) 3.4, 9.1 Hz), 4.22 (2H, dd, J ) 3.4, 12.2

Hz), 4.72 (2H, dd, J ) 6.6, 15.0 Hz), 4.84 (2H, dd, J ) 6.3, 10.7 Hz),

4.96 (2H, br s), 5.08 (2H, br s), 5.95 (2H, d, J ) 8.6 Hz, D₂O exch),

6.91 (2H, d, J ) 8.3 Hz), 7.23 (2H, d, J ) 8.3 Hz), 7.38 (2H, s). ¹³C

NMR (75.5 MHz) (CDCl₃) (mixture of two diastereomers): δ -4.9

(q), -4.0 (q), 16.5 (q), 17.9 (s), 18.8 (q), 24.1 (t), 25.7 (q), 28.0 (q),

JA952666C

Article Doi

Stereocontrolled total synthesis of (+)-paraherquamide B

DOI: 10.1021/ja952666c

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