Synthesis of conduramines from N-tert-butoxycarbonylpyrrole

J . Org. Chem. 1998, 63, 3235-3250

3235

Syn th esis of Con d u r a m in es fr om N-ter t-Bu toxyca r bon ylp yr r ole^†

Regis Leung-Toung,^‡Yanzhou Liu, J oseph M. Muchowski,* and Yu-Lin Wu^§

Syntex Research, Institute of Organic Chemistry, 3401 Hillview Avenue, Palo Alto, California 94304

Received October 15, 1997

Two related synthetic strategies were devised to convert the Diels-Alder adduct 3c of Boc-pyrrole

and p-toluenesulfonylacetylene into various racemic and optically pure conduramines. One process

consists of the regio- and stereoselective hydroxylation of 3c to the tri- and dihydroxylated azabicyclo-

[2.2.1]heptane derivatives 10b (Scheme 2) and the exo-endo mixture 13-14 (Scheme 3). Anionic

fragmentation of 10b (methylmagnesium bromide) and of the 13-14 sulfone mixture (lithium bis-

(trimethylsilyl)amide) generated the corresponding tri- and dihydroxylated aminocyclohexenes 17

and 16 (Scheme 3). Compound 17 is an aminocyclitol with a stereochemistry and partial aminotriol

sequence identical to that found in neoinosamine. Compound 16 served as a source of the protected

and free aminodiols 35b and 35a (Scheme 6), which were stereospecifically epoxidized to 36 (Scheme

6) and 40 (Scheme 7). Phenylselenide cleavage of these epoxides provided 37 (Scheme 6) and 41a

(Scheme 7), which after selenoxide cycloelimination and protecting group manipulation were

converted into (()-conduramine C-1 (39a , Scheme 6) and the previously unreported, all-cis-

conduramine D-1 (43a , Scheme 7). In a second process, anionic fragmentaion of the bicyclic system

is effected prior to introduction of the hydroxyl groups, as exemplified by the high-yielding conversion

of the exo-endo mixture of azabicycloheptenes 11 and 12 into the aminocyclohexadiene 15 (Scheme

3). Osmate catalyzed cis-dihydroxylation of the derived bis-Boc derivative 20 (Scheme 4) led

stereospecifically to the R-cis-diol 21 which was transformed into (()-conduramine A-1 (27a ) and

its tetraacetyl derivative 27b via the epoxy compound 24. On the other hand, peracid oxidation of

the diene 15 gave the â-epoxide 28 (Scheme 5) which was cleaved to the trans-diol 29 with aqueous

sulfuric acid. This diol was converted into (()-conduramine F-1 (34a ) and its tetraacetyl derivative

(34b) by a reaction sequence similar to that used for the other conduramine syntheses. Fractional

crystallization of the diastereomeric mixture of Michael adducts obtained from (()-3c and (-)-

methyl lactate gave (-)-44a and (-)-45a both in g47% yield (Scheme 8). Both the carboxylic acid

(+)-44b and the primary alcohol (+)-46 derived from (-)-44a were converted into (-)-3c with excess

methylmagnesium bromide (ca. 40% overall yield). In the same way (-)-45a was transformed into

optically pure (+)-3c. (-)-3c and (+)-3c were then converted into (-)-conduramine C-1 [(-)-39a ]

and (+)-conduramine D-1 [(+)-43a ] by procedures identical to those used for the racemic compounds.

In tr od u ction

useful preparative routes to these compounds^3a,e,o,8and

their derivatives.^{3d,f-h,j-l,n,4-7,9}Hudlicky et al. (op. cit.)

have devised a very effective synthetic strategy which

produces either (+)- or (-)-conduramines from a single,

optically pure 1-halo-cis-2,3-dihydrobenzene-2,3-diol. The

Conduramines are purely synthetic aminocyclohexen-

etriols¹formally derived from conduritols. (Two condu-

ritols are naturally occurring. See, Balci et al.,^1bp 3724

and references cited therein.) Some conduramines have

significant glycosidase inhibitory activity,²but they are

of much greater importance as synthetic precursors of

amino- and diaminocyclitols,³many of which constitute

the aglycon portions of the therapeutically useful ami-

noglycoside antibiotics. In addition, conduramines have

been utilized as intermediates in the preparation of

azasugars,⁴aminosugars,⁵sphingosines,⁶and narcissus

alkaloids.⁷Given the importance of conduramines as

synthetic building blocks, it is not surprising that so

much effort has been devoted to the development of

(3) (a) Nakajima, M.; Hasegawa, A.; Kurihara, N. Chem. Ber. 1962,

95, 2708. (b) Nakajima, M.; Kurihara, N.; Hasegawa, A. Liebigs Ann.

Chem. 1965, 689, 243. (c) Nakajima, M.; Hasegawa, A.; Kurokawa,

T. Liebigs Ann. Chem. 1965, 689, 229. (d) Kresze, G.; Dittel, W.;

Melzer, H. Liebigs Ann. Chem. 1981, 224. (e) Kresze, G.; Dittel, W.

Liebigs Ann. Chem. 1981, 610. (f) Paulsen, H.; Heiker, F. R. Liebigs

Ann. Chem. 1981, 2180. (g) Mu¨ller, K.-H.; Kaiser, C.; Pillat, M.;

Zipperer, B.; Froom, M.; Fritz, H.; Hunkler, D.; Prinzbach, H. Chem.

Ber. 1983, 116, 2492. (h) Knapp, S.; Sebastian, M. J .; Ramanthan, H.

J . Org. Chem. 1983, 48, 4786. (i) Paulsen, H.; Ro¨ben, W. Liebigs Ann.

Chem. 1985, 974. (j) Schubert, J .; Schivesinger, R.; Knothe, L.;

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M.; Nakazawa, K.; Ogawa, S. J . Chem. Soc., Chem. Commun. 1989,

436; J . Org. Chem. 1991, 56, 2976. (l) Braun, H.; Burger, W.; Kresze,

G.; Schmidtchen, F. P.; Vaerman, J . L.; Viehe, H. G. Tetrahedron:

Asymmetry 1990, 1, 403. (m) Beier, B.; Schu¨rrle, K.; Werbitzky, O.;

Piepersberg, W. J . Chem. Soc., Perkin Trans. 1 1990, 2255. (n) Cambie,

R. C.; Renner, N. D.; Rutledge, P. S.; Woodgate, P. D. Aust. J . Chem.

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Chem. 1993, 71, 2102. (q) Arjona, O.; de Rios, A.; Plumet, J .; Saez, B.

Tetrahedron Lett. 1995, 36, 1319.

^†Dedicated to Dr. Yvon G. Perron, mentor and friend, on the

occasion of his 73rd birthday.

^‡Syntex Research Postdoctorate Fellow, 1992-1994.

^§Syntex Research Visiting Professor, 1992.

(1) (a) Posternack, T. The Cyclitols; Holden-Day Inc: San Francisco,

1965; pp 211-212. (b) Balci, M.; Su¨tbeyaz, Y.; Sac¸en, H. Tetrahedron

1990, 46, 3715.

(2) (a) Umezawa, W. Adv. Carbohydr. Chem. Biochem. 1974, 30, 111.

(b) Legler, G.; Herrchen, M. FEBS Lett. 1981, 135, 139. (c) Legler,

G.; Bause, E. Carbohydr. Res. 1973, 28, 45. (d) Legler, G.; Lotz, W.

Hoppe-Seyler’s Z. Physiol. Chem. 1973, 354, 243. (e) Legler, G. Mol.

Cell. Biochem. 1973, 2, 31.

(4) (a) Hudlicky, T.; Rouden, J .; Luna, H. J . Org. Chem. 1993, 58,

985; Rouden, J .; Hudlicky, T. J . Chem. Soc., Perkin Trans. 1 1993,

1095; Hudlicky, T.; Rouden, J .; Luna, H.; Allen, S. J . Am. Chem. Soc.

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Miller, M. W.; Dwiahy, R. L. Tetrahedron Lett. 1995, 36, 653.

Published on Web 04/28/1998

3236 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

Sch em e 1

diols are obtained from the corresponding inexpensive

halobenzenes by fermentation with a strain of Pseudomo-

nas putida. We were interested in examining a similar

strategy whereby the 7-azabicyclo[2.2.1]heptadiene de-

rivative 3 (Scheme 1) might serve as a universal condu-

ramine precursor. The bicyclic system was expected to

exert predictable control over the stereochemistry of

hydroxylation, after which anionic fragmentation¹⁰initi-

ated by the sulfonyl group would provide an hydroxylated

aminocyclohexene derivative 4 suitable for elaboration

to various conduramines. Alternatively, fragmentation

of the bicyclic system, after conjugate reduction of the

R,â-unsaturated sulfone, would lead to the aminocyclo-

hexadiene derivative 5, a potential conduramine progeni-

tor in which all the ring carbon atoms are chemically

differentiated. If, in addition, 3 could by some means be

generated in both enantiopure forms, then it could

provide access, in principle, to any desired enantiopure

conduramine.

Resu lts a n d Discu ssion

A. Syn th esis of th e 7-Aza bicyclo[2.2.1]h ep ta d ien e

Der iva tives (3). Altenbach, et al.^13afirst described the

synthesis of 3a by the Diels-Alder reaction of N-

methoxycarbonylpyrrole (1a ) with ethynyl-p-tolyl sulfone

(2a ). We found that one set of optimum conditions to

effect the cycloaddition reaction was to heat a 2:1 molar

ratio of the alkoxycarbonylpyrrole and the acetylenic

sulfone without solvent at 75-90 °C for 16-48 h.^13b

Removal of the excess pyrrole derivative (recoverable) by

column chromatography on silica gel gave the azabicyclo-

[2.2.1]heptadienes 3a -e in good yields. For example, by

using these conditions, the Boc derivative 3c was easily

and routinely prepared in over 80% yield on a 100 g scale.

It is important to note that the diastereomeric mixture

3d derived from (-)-N-menthyloxycarbonylpyrrole (1d )

could not be induced to crystallize, and it could not be

separated by chromatographic techniques. Thus, other

means of obtaining both enantiomeric forms of the

azabicyclo[2.2.1]heptadienes had to be devised.

One of the disadvantages of using 3 as conduramine

progenitors is that the room-temperature NMR spectra

of these compounds are complicated because of restricted

rotation about the NCO bond. The spectra do become

simpler when they are recorded at higher temperatures

(310-410 °K). This operation was inconvenient, but it

was vital in the confirmation of the stereochemistry of

the bicyclic compounds derived from 3 by functionaliza-

tion of one or both double bonds. This operation was also

necessary for the Boc-protected cyclohexenylamines ob-

tained by anionic fragmentation of the bicyclic com-

pounds and for the Boc-protected compounds derived

from them.

This article gives a full description of the successful

utilization of 3c¹¹for the synthesis of both racemic and

optically pure conduramines.¹²

(5) (a) Lehman, J .; Moritz, A. Liebigs Ann. Chem. 1991, 937. (b)

Pitzer, K.; Hudlicky, T. Synlett 1995, 803.

(6) Hudlicky, T.; Nugent, T.; Griffeth, W. J . Org. Chem. 1994, 59,

7944.

(7) (a) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991,

32, 4525. (b) Hudlicky, T.; Olivo, H. F.; McKibben, B. J . Am. Chem.

Soc. 1994, 116, 5108; Hudlicky, T.; Olivo, H. F. J . Am. Chem. Soc. 1992,

114, 9694. (c) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J . Am. Chem.

Soc. 1995, 117, 3643. (d) Tian, X.; Maurya, R.; Ko¨nigsberger, K.;

Hudlicky, T. Synlett 1995, 1125.

(8) (a) Paulsen, H.; Ro¨ben, W.; Heiker, F. R. Chem. Ber. 1981, 114,

3242. (b) Werbitzky, O.; Kleir, K.; Felber, H. Liebigs Ann. Chem. 1990,

267. (c) Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen, C.; Nugent,

T.; Price, J . D. J . Chem. Soc., Perkin Trans. 1 1991, 2907. (d) Hudlicky,

T.; Olivo, H. F. Tetrahedron Lett. 1991, 32, 6077. (e) J ohnson, C. R.;

Ple´, P. A.; Su, L.; Heeg, M. J .; Adams, J . P. Synlett 1992, 388. (f)

Allemann, S.; Vogel, P. Helv. Chim. Acta 1994, 77, 1. (g) Trost, B. M.;

Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737.

(9) (a) Kresze, G.; Sabuni, M. Z. Naturforsch. 1987, 42c, 446. (b)

Klier, K.; Kresze, G.; Werbitzky, O.; Simon, H. Tetrahedron Lett. 1987,

28, 2677. (c) Cotterill, I. C.; Roberts, S. M.; Williams, J . O. J . Chem.

Soc., Chem. Commun. 1988, 1628; Mahon, M. F.; Molloy, K.; Pittol, C.

A.; Pryce, R. J .; Roberts, S. M.; Ryback, G.; Sik, V.; Williams, J . O.;

Winders, J . A. J . Chem. Soc., Perkin Trans. 1 1991, 1255. (d) Martin,

S. F.; Hartmann, M.; J osey, J . A. Tetrahedron Lett. 1994, 33, 3583.

(10) (a) Kozikowski, A. P.; Kuniak, M. P. J . Org. Chem. 1978, 43,

2083. (b) Brion, F. Tetrahedron Lett. 1982, 23, 5299. (c) Campbell,

M. M.; Kaye, A. D.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron Lett.

1984, 25, 1629. (d) Rajapaksa, D.; Keay, B. A.; Rodrigo, R. Can. J .

Chem. 1984, 62, 826 and refs cited therein. (e) Keay, B. A.; Rajapaksa,

D.; Rodrigo, R. Can. J . Chem. 1093, and refs cited therein. (f) Grieco,

P. A.; Liz, R.; Zelle, R. E.; Finn, J . J . Am. Chem. Soc. 1986, 108, 5906.

(g) J ung, M. E.; True, V. C. Tetrahedron Lett. 1988, 29, 6059. (h)

Acen˜a, J . L.; Arjona, O.; Iradier, F.; Plumet, J . Tetrahedron Lett. 1996,

37, 105. (i) Evans, D. A.; Barnes, D. M. Tetrahedron Lett. 1997, 38,

57.

B. Fu n ction alization of 3c. Oxygen ation (Sch em e

2). Compound 3c is admirably suited for site specific

oxygenation because of the greatly different electron

density of the double bonds. Thus, osmium tetroxide

catalyzed hydroxylation¹⁴occurred regiospecifically at the

more nucleophilic double bond to give the exo-cis-diol 7

exclusively (73%). This compound was produced in some-

what better yield (81%)¹⁵when the dihydroxylation was

conducted in two steps via the phenyl boronate 6. The

(12) For a preliminary communication on some aspects of this study

see: Leung-Toung, R.; Liu, Y.; Muchowski, J . M.; Wu, Y.-L. Tetrahe-

dron Lett. 1994, 35, 1639.

(13) (a) Altenbach, H. J .; Blech, B.; Marco, J . A.; Vogel, E. Angew.

Chem., Int. Ed. Engl. 1982, 21, 778. (b) The cycloaddition reaction

proceeds with equal or better efficiency using a 1:2 molar ratio of 4

and 5. Chen, Z.; Trudell, M. L. Tetrahedron Lett. 1994, 35, 9649.

(14) Van Rheenan, V.; Kelley, R. C.; Cha, D. Y. Tetrahedron Lett.

1976, 1973.

(11) After some initial studies using 1b, we chose to use 1c as the

starting material because the Boc moiety gave rise to simpler NMR

spectra and because of its facile removal with trifluoroacetic acid.

(15) Iwasawa, N.; Kato, T.; Narasaka, K. Chem. Lett. 1988, 1721.

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3237

Sch em e 2^a

a

Reagents and conditions: (a) OsO₄, NMO/NaHCO₃, t-BuOH, H₂O, THF/rt; (b) OsO₄, NMO, PhB(OH)₂/t-BuOH, CH₂Cl₂/rt; (c) 30%

H₂O₂/THF, CH₂Cl₂, H₂O/rt; (d) Me₂C(OMe)₂, Me₂CO/TsOH/rt; (e) syn-PhCHdNOH, PhCHdNONa (cat.)/DMSO/rt; (f) NaBH₄, TFA/THF,

reflux.

regio- and stereochemistry of this hydroxylation was

readily apparent from the ¹H NMR spectra of the phenyl

boronate 6, the diol 7, or the acetonide 8, all of which

still retained an absorption for the olefinic hydrogen H-3

at ca. δ 7.2, and also showed characteristically small¹⁶

values for J _1,6and J _4,5(Table 1). Hydroxylation of the

less nucleophilic 2,3-double bond of the bicyclic system

could also be readily effected. Specifically, conjugate

addition of syn-benzaldoxime to 8 at room temperature,

catalyzed by sodium benzaldoximate, gave a 1:7.5 mix-

ture of the exo- and endo-oximates 9 and 10a , the

stereochemistries of which were deduced from NOE

effects and the appropriate J values (Table 1). It is not

known whether this isomer ratio is a consequence of

kinetic or thermodynamic control. Reduction of the endo-

oximate 10a with sodium trifluoroacetoxyborohydride,

which is known to reductively cleave oxime ethers,¹⁷gave

the 3-endo-hydroxy-2-exo-tosyl compound 10b in high

yield. This is another example of the use of syn-

benzaldoxime as a formal OH^-equivalent.¹⁸

2. An ion ic Rin g Clea va ge of th e F u n ction a lized

7-Aza bicyclo[2.2.1]h ep ta n e Der iva tives. Syn th esis

of a (()-Con d u r a m in e C Der iva tive w ith a 3,5,6-

Tr ih yd r oxy-4-a m in o Sequ en ce (Sch em e 3). One

strategy which we envisioned using to trigger fragmenta-

tion of the bicyclic systems required a hydrogen atom R

to the sulfone moiety. Compound 10b is already ap-

propriately functionalized for this purpose, but 3c and 8

are not. These compounds were brought to the required

oxidation level by reduction with excess methanolic

sodium borohydride. In each case, easily separable

mixtures of exo- and endo-sulfones were obtained for

which the exo:endo ratios differed considerably from

system to system, e.g., 11:12 ) 0.13; 13:14 ) 10. The

exo isomer is the thermodynamically more stable one,

at least for 13. For example, generation of the anion from

the endo-sulfone 14 with lithium bis(trimethylsilyl)amide

in THF at -78 °C, followed by quenching at this tem-

perature after 1 h, gave 13 exclusively. The sulfone

stereochemistry is, thus, inconsequential because of this

equilibration and because the equilibrium will shift

constantly in the direction of the anion undergoing

fragmentation.¹⁰Indeed, addition of THF solutions of 11

and 12 or of 13 and 14 to 1.5-2 equiv of lithium bis-

(trimethylsilyl)amide^10bat -78 °C, followed by warming

to rt cleanly gave the fragmentation products 15 and 16,

respectively, in yields approaching 80%.

Whereas lithium bis(trimethylsilyl)amide efficiently

triggered anionic cleavage of 11-14, it was completely

without effect on the endo-hydroxy compound 10b, even

at 50 °C. Excess n-butyllithium in THF, both alone¹⁹and

admixed with sodium tert-butoxide, gave similar results.

Surprisingly, however, the addition of excess (6 equiv)

methylmagnesium bromide to a THF solution of 10b at

rt produced the fragmentation product 17 in over 80%

yield.²⁰Although it was not done, desulfonylation and

deprotection of 17 would generate an aminotriol with the

stereochemistry of a conduramine C, but with a 4-amino-

3,5,6-triol substituent sequence, identical to that found

in neoinosamine.^1aThis approach to aminocyclitols, in

which an hydroxyl group is installed at C-3 prior to

fragmentation of the azabicyclo[2.2.1]heptane system,

merits further study.

C. Syn th esis of (()-Con d u r a m in es fr om (()-1-

ter t-Bu toxyca r bon yla m in o-5-p-tolu en esu lfon yl-2,4-

cycloh exa d ien e (15). 1. (()-Con d u r a m in e A-1

(Sch em e 4). The cyclohexadiene derivative 15 is a

substrate in which chemoselective functionalization of the

double bonds is anticipated to be facile. Although the

synthesis of conduramines could, in principle, be initiated

at either double bond, we chose to functionalize the

nonconjugated one first because the proximal tert-bu-

toxycarbonylamino group was expected to exert greater

stereochemical control over reactions at this site than

over those at the more remote double bond.

The synthesis of (()-conduramine A-1 from 15 required

the introduction of cis-vicinal hydroxyl groups trans to

the protected amino moiety. Osmate catalyzed hydroxy-

lation of this diene gave a 1:1 mixture of cis-diols 18 (see

also Scheme 6) and 19a which was converted into a

mixture of acetonides, one of which was identical to the

all-cis-acetonide 16 (Scheme 3). In contrast, the easily

(16) Pretsch, E.; Simon, W.; Seibl, J .; Clerc, T. Tables of Spectral

Data for Structure Determination of Organic Compounds, 2nd English

Ed.; Springer-Verlag: Berlin, 1989; p H190.

(17) Umino, N.; Iwakuma, T.; Ikezaki, M.; Itoh, N. Chem. Pharm.

Bull. 1978, 26, 2897.

(18) Go´mez, V.; Pe´rez, Medrano, A.; Muchowski, J . M. J . Org. Chem.

1994, 59, 1219 and refs therein.

(19) Anion formation did occur, since quenching with D₂O gave 10b

with >95% deuterium at C-2.

(20) This cleavage method was discovered near the end of this study.

We hope to study this process in detail in the future. A referee has

suggested that this reactivity difference might be a function of the

preferred octahedral coordination of magnesium versus that of lithium

(tetrahedral).

3238 J . Org. Chem., Vol. 63, No. 10, 1998

Ta ble 1. ¹H NMR Sp ectr a l Da ta for Som e 7-Aza bicyclo[2.2.1]h ep tyl Com p ou n d s

Leung-Toung et al.

NOE’s

solvent^a

compd no.

(T, K)

δ (ppm)

J _Values(Hz)

(-)-3c

A (330)

1.31 (s, 9H), 2.43 (s, 3H), 5.18 (m, 1H), 5.34 (bq, 1H),

6.85 (dd, 1H), 6.96 (dd, 1H), 7.32 (d, 2H),

7.49 (dd, 1H), 7.74 (d, 2H)

J _1,3) 0.7, J _1,4) 1.8, J _1,5) 0.7,

J _1,6) 2.5, J _3,4) 2.4, J _4,5) 2.5,

J _4,6< 0.5, J _5,6) 5.3

6

(-)-7

(-)-8

9

A (probe)^b1.14 (s, 9H), 2.44 (s, 3H), 4.60 (dd, 1H), 4.75 (dd, 1H),

4.81 (m, 1H), 4.94 (m, 1H), 7.05 (dd, 1H),

J _1,3) 0.5, J _1,6) 0.7, J _3,4) 2.2,

J _4,5) 0.5, J _5,6) 5.5

7.31-7.48 (m, 5H), 7.76 (d, 2H), 7.82 (d, 2H)

1.18 (s, 9H), 2.42 (s, 3H), 3.57 (d, 1H), 3.67 (dd, 1H),

4.38 (dd, 1H), 4.48 (t, 1H), 7.13 (d, 1H), 7.47 (d, 2H),

7.75 (d, 2H)

1.25 (s, 9H), 1.29 (s, 3H), 1.43 (s, 3H), 2.44 (s, 3H),

4.32 (d, 1H), 4.49 (d, 1H), 4.64 (dd, 1H),

4.79 (dd, 1H), 7.02 (dd, 1H), 7.35 (d, 2H), 7.78 (d, 2H)

1.29 (s, 3H), 1.36 (s, 12H), 2.33 (s, 3H), 3.72 (dd, 1H),

4.37 (d, 1H), 4.43 (d, 1H), 4.47 (dd, 1H), 4.72 (d, 1H),

5.02 (d, 1H), 7.32-7.44 (m, 7H), 7.82 (d, 2H), 7.93 (s, 1H)

1.21 (s, 3H), 1.30 (s, 3H), 1.41 (s, 9H), 2.35 (s, 3H),

3.34 (d, 1H), 4.41 (bm, 1H), 4.47 (bm, 1H), 4.48 (d, 1H),

4.59 (d, 1H), 4.91 (t, 1H), 7.39-7.44 (m, 5H),

7.53-7.56 (m, 2H), 7.79 (d, 2H), 8.12 (s, 1H)

1.22 (s, 3H), 1.31 (s, 3H), 1.40 (s, 9H), 2.43 (s, 3H),

2.89 (d, 1H), 4.12 (bm, 1H), 4.22 (bm, 1H), 4.32 (d, 1H),

4.43 (bm, 1H), 4.72 (d, 1H), 7.42 (d, 2H), 7.77 (d, 2H)

1.32 (s, 9H), 1.52 (dd, 1H), 2.08 (dt, 1H), 2.41 (s, 3H),

3.21 (dd, 1H), 4.62 (m, 1H), 4.76 (d, 1H), 6.38 (m, 1H),

6.47 (dd, 1H), 7.43 (d, 2H), 7.75 (d, 2H)

B (360)

A (330)

B (380)

B (390)

J _1,4) 1.7, J _3,4) 2.3, J _5,6) 6.0

J _1,3) 0.6, J _1,4) 0.6, J _1,6e 0.5,

J _3,4) 2.3, J _5,6) 5.5

J _1,2) 5.0, J _1,4) 1.8, J _2,3) 3.4,

J _5,6) 5.5

1 T 2, 3 T 4,

3 T 5, 5 T 6

10a

J _1,4) 1.6, J _2,3) 4.1, J _3,4) 4.4,

J _5,6) 5.4

2 T 3, 2 T 6

10b

11

B (370)

B (330)

J _2,3) 4.1, J _5,6) 5.4

2 T 3, 2 T 6,

3 T 4, 4 T 5,

5 T 6

J _1,6) 2.1, J _2,3-endo) 8.5,

J _2,3exo) 4.3, J _3exo-3endo) 12.4,

J

_3exo,4-) 4.2, J _4,5≈ 2,

J _5,6) 5.6

12

(-)-13

(+)-14

B (330)

B (410)

A (330)

1.32 (s, 9H), 1.48 (m, 1H), 2.18 (m, 1H), 2.43 (s, 3H),

3.86 (m, 1H), 4.55 (m, 1H), 4.66 (m, 1H), 6.32 (dd, 1H),

6.50 (dd, 1H), 7.45 (d, 2H), 7.76 (d, 2H)

J _1,2) 3.9, J _1,4< 1, J _1,6) 2.0,

J _2,3-exo) 9, J _2,3-endo) 4.5,

J _3-exo-endo) 11.9, J _3-exo,4) 3.6,

J _4,5) 2.2, J _5,6) 5.8

J _2,3-exo) 5.3, J _2,3-endo) 8.7,

J _3-exo,endo) 13.3, J _3-exo,4) 5.3,

J _5,6) 5.4

1.16 (s, 3H), 1.27 (s, 3H), 1.39 (bs, 9H), 1.64 (q, 1H),

2.00 (dt, 1H), 2.42 (s, 3H), 3.31 (dd, 1H), 4.16 (d, 1H),

4.18 (bm, 1H), 4.20 (d, 1H), 4.28 (bm, 1H), 7.42 (d, 2H),

7.75 (d, 2H)

1.31 (s, 3H), 1.40 (s, 3H), 1.41 (s, 9H), 1.77 (dd, 1H),

2.01 (ddd, 1H), 2.45 (s, 3H), 3.47 (ddd, 1H), 4.30 (dd, 1H),

4.33 (d, 1H), 4.38 (dd, 1H), 5.13 (d, 1H), 7.36 (d, 2H),

2.77 (d, 2H)

2 T 6, 2 T 3-endo

J _1,2) 4.9, J _1,4) 0.9, J _2,3-exo) 11.3, 1 T 2, 1 T 6,

J _2,3-endo) 5.9, J _3-exo-endo) 13.0,

J _3-exo,4) 5.4, J _5,6) 5.5

2 T 3-exo,

3-exoT3-endo,

3-endo T 4,

3-endo T 5, 5 T 6

(-)-44a

(-)-45a

A (325)

1.26 (d, 3H), 1.39 (s, 9H), 2.45 (s, 3H), 3.52 (t, 1H),

3.74 (s, 3H), 3.99 (bd, 1H), 4.10 (m, 1H),

J _1,2) 3.6, J _1,6) 2.1, J _2,3) 2.9,

J _4,5) 2.5, J _5,6) 5.8

4.58 (bm, 1H), 4.83 (m, 1H), 6.37 (dd, 1H),

6.49 (dd, 1H), 7.36 (d, 2H), 7.75 (d, 2H)

1.39 (d, 3H), 1.40 (s, 9H), 2.45 (s, 3H), 3.72 (s, 3H),

3.74 (t, 1H), 4.15 (d, 1H), 4.20 (q, 1H),

4.65 (bm, 1H), 4.75 (bm, 1H), 6.36 (dd, 1H),

6.57 (dd, 1H), 7.34 (d, 2H), 7.79 (d, 2H)

J _1,2= 3.3, J _1,6) 2.1, J _2,3) 2.7,

J _4,5) 2.6, J _5,6) 5.9

(+)-46

(-)-47

A (330)

0.83 (bs, 3H), 1.41 (s, 9H), 2.44 (s, 3H), 3.38 (m, 1H),

3.46 (t, 3H), 4.04 (d, 1H), 4.75 (bt, 1H), 4.82 (bs, 1H),

6.34 (dd, 1H), 6.53 (dd, 1H), 7.37 (d, 2H), 7.77 (d, 2H)

1.15 (d, 3H), 1.39 (s, 9H), 2.44 (s, 3H), 3.37 (dd, 1H),

3.49 (dd, 1H), 3.54 (t, 1H), 3.67 (m, 1H), 4.15 (d, 1H),

4.56 (bs, 1H), 4.65 (bs, 1H), 6.37 (dd, 1H), 6.48 (dd, 1H),

7.39 (d, 1H), 7.78 (d, 2H)

J _1,2= 3.3, J _1,6) 2.1, J _2,3) 2.7,

J _4,5) 2.8, J _5,6) 5.9,

1 T 2, 2 T 3,

3 T 4

J _AB) 12 (CH₂O)

J _1,2) 3.5, J _1,6) 1.6, J _2,3) 2.9,

1 T 2, 1 T 6,

2 T 3, 3 T 4,

3 T 5

J _4,5) 2.2, J _5,6) 5.8,

J _AB) 11.9 (CH₂O), J _AX) 6.7,

J _BX) 3.4

a

b

A ) CDCl₃, B ) DMSO-d₆. Single rotamer at probe temperature. ^cTwo rotamers at this temperature.

prepared bis-Boc compound 20 underwent exclusive cis-

dihydroxylation trans to the exceedingly voluminous bis-

Boc moiety to produce 21 in over 90% yield. This

stereochemistry is assured by the ca. 11 Hz J value for

the trans diaxial hydrogens at C-4,5 (Table 2). Reaction

of 21 with 6% sodium amalgam in buffered methanol

solution²¹effected reductive removal of the arylsulfonyl

group and hydrolysis to the oily mono-Boc olefinic diol

22. Completion of the synthesis of (()-conduramine A-1

required the introduction of the third hydroxyl group.

Therefore the diol 22 was converted into the acetonide

23 which ensured that peracid oxidation of the double

bond occurred without allylic oxygen participation. The

epoxide 24, so obtained, was cleaved with lithium phenyl

selenide, and the phenylselenyl compound 25 was con-

verted into the conduramine A-1 derivative 26 by the

selenoxide cycloelimination process.²²Aqueous trifluo-

roacetic acid removed the protecting groups from 26, and

addition of aqueous ammonia to this solution liberated

(()-conduramine A-1 (27a ) which was converted into the

crystalline tetracetyl derivative 27b. The ¹³C NMR

spectrum of 27b was identical to that reported^8bfor the

tetracetyl derivative of (+)-conduramine A-1.

2. (()-Con d u r a m in e F -1 (Sch em e 5). Three of the

four substituents in conduramine F-1 are oriented cis,

and the C-5 hydroxyl group is trans disposed. It was

expected that the necessary cis-3-amino-4-oxy stereo-

chemistry would result on peroxycarboxylic acid epoxi-

dation of the Boc-diene 15 because of hydrogen bonding

of the peracid to the Boc moiety in the transition state

for epoxidation.²³Indeed, reaction of 15 with m-chlorop-

eroxybenzoic acid in a dichloromethane solution gave a

9:1 mixture of epoxides (>90% yield), the major compo-

nent of which was 28, as judged from the small J _3,4and

J _4,5values (Table 2). Sulfuric acid catalyzed hydrolysis

of 28 gave a single diol (29) which was reductively

(22) (a) Sharpless, K. B.; Lauer, R. F. J . Am. Chem. Soc. 1973, 95,

2697. (b) Reich, H. J .; Wollowitz, S.; Trend, J . E.; Chow, F.; Wendle-

born, D. F. J . Org. Chem. 1978, 43, 1697.

(21) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.

Tetrahedron Lett. 1976, 3477.

(23) J enmalm, A.; Berts, W.; Luthman, K.; Csoregh, I.; Hacksell,

U. J . Org. Chem. 1995, 60, 1026 and refs cited therein.

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3239

Sch em e 3^a

a

Reagents and conditions: (a) NaBH₄/MeOH/0 °C; (b) Li(NTMS)₂/THF/-78 to 0 °C; (c) MeMgBr/THF/rt.

Sch em e 4^a

a

Reagents and conditions: (a) OsO₄, NMO/NaHCO₃, t-BuOH, H₂O, THF/rt; (b) Me₂C(OMe)₂, Me₂CO/TsOH, rt; (c) (Boc)₂O/cat. 4-DMAP/

MeCN; (d) 6% Na, Hg/Na₂HPO₄/MeOH, THF/-12 °C; (e) MCPBA/NaHCO₃/CH₂Cl₂; (f) (PhSe)₂/n-BuLi/THF; (g) H₂O₂/(i-Pr)₂NEt/CH₂Cl₂/0

°C then THF/∆; (h) TFA, H₂O/CH₂Cl₂; (i) NH₃/MeOH; (j) Ac₂O/Py, cat. 4-DMAP.

desulfonylated (to 30a ) and then diacetylated to 30b. The

coupling constants J _3,4) 4.7 Hz and J _4,5) 2.7 Hz (Table

2) for 30b leave no doubt that hydrolysis of 28 had

occurred with the expected²⁴regio- and stereochemical

control. Compound 30b was then converted into (()-

conduramine F-1 (34a ) by a reaction sequence analogous

to that used for the synthesis of (()-conduramine A-1. It

was fully characterized as the crystalline, known^3etet-

raacetate 34b.

D. Syn th esis of (()-Con d u r a m in es fr om th e (()-

Aceton id e of a ll-cis-1-ter t-Bu toxyca r bon yla m in o-

2,3-dih ydr oxy-5-p-tolu en esu lfon ylcycloh ex-4-en e (16).

1. (()-Con d u r a m in e C-1 (Sch em e 6). The all-cis-

acetonide 35b, used for the synthesis of (()-conduramine

(24) Carless, H. A. J . Tetrahedron: Asymmetry 1992, 3, 795 (See

especially pp 805-809).

3240 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

Ta ble 2. NMR Sp ectr a l Da ta of Con d u r a m in es, Con d u r a m in e Der iva tives, a n d Con d u r a m in e P r ecu r sor s

solvent^a

(T, K)

compd no.

δ (ppm)

J _Values(Hz)

NOE’s

15

A (330)

1.38 (s, 9H), 2.43 (s, 1H), 2.52 (dq, 1H), 2.60 (dq, 1H),

4.35 (bq, 1H), 6.04 (dd, 1H), 6.18 (ddd, 1H),

7.03 (m, 1H), 7.31 (d, 2H), 7.74 (d, 2H)

J _2,3) 5.6, J _2,4< 1, J _2,6a) 2.9,

J _2,6e) 2.0, J _3,4) 9.4, J _3,5)1.1,

J _4,5) 4.8, J _5,6a) 8.2, J _5,6e) 7.2,

J _6a,e) 17.5

16

17

A (310)

B (350)

1.20 (s, 3H), 1.36 (s, 3H), 1.42 (s, 9H), 2.10 (tdd, 1H),

2.44 (s, 3H), 2.55 (dd, 1H), 3.96 (bq, 1H),

4.28 (dd, 1H), 4.76 (m, 1H), 4.85 (bd, 1H),

6.75 (t, 1H), 7.34 (d, 2H), 7.73 (d, 2H)

1.28 (s, 3H), 1.31 (s, 3H), 1.35 (s, 9H), 2.40 (s, 3H),

3.76 (dd, 1H), 4.34 (bd, 1H), 4.39 (dd, 1H),

4.84 (ddd, 1H), 6.78 (bd, 1H), 7.38 (d, 2H),

7.73 (d, 2H)

J _2,3) 2.8, J _2,6a) 3.0, J _3,4) 5.2,

J _3,6a) 2.3, J _4,5) 2.2, J _5,6a) 10.4,

J _5,6e) 5.5, J _6a,e) 16.3

2 T 3, 3 T 4,

3 T 5(w), 3 T 6a,

4 T 5, 5 T 6e,

6a T 6e, 6a T NH

2 T 3, 3 T 4,

J _2,3) 3.0, J _2,6) 1.2, J _3,4) 5.3,

J _3,6) 1.5, J _4,5) 3.1, J _5,6) 7.5

3 T 6, 4 T 5,

5 T 6 (w), 2 T OH,

5 T OH (w)

(+)-18

B (360)

A (325)^b

1.35 (s, 9H), 2.14 (m, 1H), 2.23 (m, 1H), 2.40 (s, 3H),

3.58 (m, 1H), 3.76 (dd, 1H), 4.29 (m, 1H),

6.58 (m, 1H), 7.41 (d, 2H), 7.68 (d, 2H)

1.43 (s, 18H), 2.41 (s, 3H), 2.64 (ddd, 1H), 2.74 (ddd, 1H),

5.17 (ddt, 1H), 5.88 (dd), 5.98 (ddd, 1H),

6.94 (ddd, 1H), 7.30 (d, 2H), 7.74 (d, 2H)

J _2,3) 3.5, J _2,6a) 1.8, J _2,6e) 1.3,

J _3,4) 3.7, J _3,6a) 3.3, J _4,5) 1.8,

J _5,6a) 9.5, J _5,6e) 6.1, J _6a,e) 16.8

J _2,3) 5.5, J _2,4) 0.9, J _2,6a) 2.5,

J _2,6e) 1.2, J _3,4) 9.8, J _3,5) 2.8,

J _4,5) 2.8, J _4,6a) 0.8, J _5,6a) 14.4,

J _5,6e) 11.4, J _6a,e) 17.2

20

21

23

A (probe)^c1.45 (s, 18H), 2.43 (s, 3H), 2.57 (dd, 1H), 2.72 (ddd, 1H),

4.12 (dd, 1H), 4.37 (dt, 1H), 4.44 (t, 1H),

J _2,3) 5.4, J _2,6a) 2.2, J _3,4) 4.2,

J _4,5) 11.2, J _5,6a) 10.8, J _5,6e) 5.7,

J _6a,e) 17.1

6.91 (dd, 1H), 7.33 (d, 2H), 7.74 (d, 2H)

A (335)

1.38 (s, 3H), 1.45 (s, 9H), 1.93 (m, 2H), 2.56 (dt, 1H),

3.84 (dt, 1H), 4.05 (dd, 1H), 4.55 (m, 1H),

4.58 (b, 1H), 5.79-5.89 (m, 2H)

J _1,2) 10.0, J _1,6a) 2.9, J _1,6e) 4.0,

J _2,3) 3.2, J _3,4) 5.9, J _3,6a) 1.4,

J _4,5) 7.7, J _5,6a) 7.6, J _5,6e) 4.9,

J _6a,e) 17.4

J _1,2) 3.9, J _1,6a) 2.8, J _1.6e< 1,

J _2,3< 1, J _2,4) 1.2, J _3,4) 5.2,

J _4,5) 3.6, J _5,6a) 5.1, J _5,6e) 2.3,

J _6a,e) 15.5

J _1,2) 10.7, J _1,6a) 11.6, J _1,6e) 4.2,

J _2,3) 6.7, J _3,4= 5.0, J _4,5= 4.0,

J _5,6a≈ 4.3, J _5,6e) 4.3, J _5,NH≈ 7.5,

J _6a,e) 14.3

J _1,2) 9.8, J _1,3) 1.8, J _1,6) 3.6,

J _2,3) 3.0, J _2,6) 2.3, J _5,6) 7.8,

J _6,NH) 6.9

J _2,3) 4.0, J _2,6a) 3.2, J _3,4) 4.2,

J _3,6e) 1.6, J _4,5< 1, J _5,6a) 10.9,

J _5,6e) 6.6, J _6a,e) 16.3

J _2,3) 4.6, J _2,6a) 2.6, J _2,6e) 1.8,

J _3,4) 3.0, J _3,6a≈ 0.9, J _4,5≈ 3.0,

J _5,6a) 9.8, J _5,6e) 5.7, J _6a,e) 17.0

J _1,2) 10.3, J _1,3) 1.0, J _1,6a) 3.1,

J _1,6e) 4.5, J _2,3) 3.5, J _2,6a≈ 2.2,

J _2,6e≈ 2.2, J _3,4) 4.7, J _4,5) 2.7,

J _5,6a≈ 7.7, J _5,6e) 5.5, J _6a,e≈ 17.4

J _1,2) 3.5, J _3,4) 8.9, J _4,5) 3.7

24

25

A (probe)^c,d1.36, (s, 3H), 1.43 (s, 12H), 2.05 (dt, 1H), 2.40 (dd, 1H),

3.11 (dd, 1H), 3.33 (m, 1H), 4.13 (bm, 1H),

1 T 2, 1 T 6a,

1 T 6e, 2 T 3,

3 T 4, 4 T 6a,

4 T 6e, 6a T 6e

1 T 3, 1 T NH,

1 T 6e, 2 T 6a,

5 T 6a, 5 T 6e

4.15 (bdd, 1H), 4.45 (d, 1H), 5.32 (bd, 1H)

A (probe)^c1.33 (s, 3H), 1.38 (s, 3H), 1.44 (s, 9H), 1.94 (ddd, 1H),

2.12 (dt, 1H), 3.00 (td, 1H), 3.56 (dd, 1H),

4.02 (m, 1H), 4.05 (dd, 1H), 4.12 (dd, 1H),

4.56 (bd, 1H), 7.27-7.38 (m, 3H), 7.58-7.62 (m, 2H)

A (probe)^c1.35 (s, 3H), 1.45 (s, 12H), 4.03 (m, 1H), 4.18 (m, 2H),

4.22 (m, 1H), 4.92 (bd, 1H), 5.80 (ddd, 1H), 5.91 (dt, 1H)

26

28

29

A (320)

B (330)^e

1.44 (s, 9H), 1.88 (ddd, 1H), 2.44 (s, 3H), 2.62 (ddd, 1H),

3.54 (m, 2H), 4.09 (bq, 1H), 7.12 (t, 1H), 7.30 (d, 2H),

7.71 (d, 2H)

1.36 (s, 9H), 2.11 (bq, 1H), 2.22 (bq, 1H), 2.42 (s, 3H),

3.62 (m, 1H), 3.68 (m, 1H), 4.12 (t, 1H), 6.72 (m, 1H),

7.44 (d, 2H), 7.69 (d, 2H)

1.45 (s, 9H), 2.05 (s, 3H), 2.06 (s, 3H), 2.12 (m, 1H),

2.50 (m, 1H), 4.19 (bm, 1H), 4.63 (bs, 1H), 5.07 (dd, 1H),

5.28 (m, 1H), 5.70 (m, 1H), 5.90 (m, 1H)

2 T 3, 2 T 6,

3 T 4, 5 T 6e,

6a T 6e

30b A (330)^e

1 T 2, 1 T 6a,

1 T 6e, 2 T 3,

3 T 4, 4 T 5,

5 T 6a, 5 T 6e

1 T 2, 1 T 6,

2 T 3, 4 T 5,

5 T 6, 3-OAc T 2

1 T 3, 1 T NH,

1 T 6e, 2 T 6a,

3 T NH, 4 T 5,

5 T 6a, 5 T 6e,

6a T 6e

31

A (probe)^c,f1.42 (s, 9H), 2.00 (s, 3H), 2.10 (s, 3H), 2.28 (m, 2H),

3.11 (d, 1H), 3.28 (m, 1H), 4.27 (m, 1H), 4.78 (dd, 1H),

5.19 (bs, 1H), 5.22 (d, 1H)

32b A (320)^g

1.44 (s, 9H), 1.60 (ddd, 1H), 1.98 (s, 3H), 1.99 (s, 3H),

2.00 (s, 3H), 2.46 (dt, 1H), 3.25 (ddd, 1H), 4.16 (sex, 1H),

4.67 (bd, 1H), 4.83 (dd, 1H), 5.00 (dd, 1H),

5.18 (dd, 1H), 7.28-7.34 (m, 3H), 7.57-7.60 (m, 2H)

J _1,2) 10.8, J _1,6a) 13.3, J _1,6e) 4.1,

J _2,3) 9.0, J _3,4) 10.3, J _4,5) 4.4,

J _5,6a) 3.4, J _5,6e≈ 3.9, J _6a,e) 14.6,

J _1,NH) 7.0

33

A (probe)^c1.45 (s, 9H), 2.03 (s, 3H), 2.06 (s, 3H), 2.07 (s, 3H),

4.55 (bm, 1H), 4.65 (m, 1H), 5.06 (dd, 1H),

J _1,2) 10.0, J _1,3) 1.5, J _1,6) 4.8,

J _2,3) 2.1, J _3,4) 7.0, J _4,5) 10.2,

J _5,6) 4.8

J _1,2) 9.8, J _1,3) 1.6, J _1,6) 4.6,

J _2,3) 2.7, J _3,4) 6.7, J _4,5) 10.0,

J _5,6) 4.6

1 T 2, 1 T 6,

2 T 3, 3 T 5,

5 T 6

5.35 (m, 2H), 5.71 (m, 1H), 5.84 (ddd, 1H)

34b A (probe)^c2.01 (s, 3H), 2.02 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H),

5.02 (m, 1H), 5.09 (dd, 1H), 5.35 (m, 1H),

5.41 (dd, 1H), 5.36 (dd, 1H), 5.60 (bm, 1H),

5.76 (ddd, 1H), 5.84 (ddd, 1H)

(+)-35a A (330)

35b A (335)^b

1.44 (s, 9H), 2.18 (m, 1H), 2.28 (m, 1H), 2.68 (bs, 2H),

3.84 (bq, 1H), 3.97 (m, 1H), 4.31 (m, 1H), 5.26 (bs, 1H),

5.60 (m, 1H), 5.74 (m, 1H)

J _1,2) 10.2, J _1,3) 1.7, J _1,6a) 3.1,

J _1,6e) 4.1, J _2,3) 4.4, J _2,6a) 2.8,

J _2,6e) 2.0, J _3,4) 4.1, J _4,5) 2.2,

J _5,6a) 8.3, J _5,6e) 4.0, J _6a,e) 17.6

J _1,2) 10.1, J _1,3) 0.7, J _1,6a) 2.5,

J _1,6e) 5.5, J _2,3) 3.1, J _2,4) 0.8,

J _2,6a) 2.6, J _2,6e) 1.1, J _3,4) 5.7,

J _4,5) 2.6, J _5,6a) 10.0, J _5,6e) 5.5,

J _6a,e) 16.5

J _1,2) 3.6, J _1,6a) 1.1, J _1,6e) 2.9,

J _2,3< 0.5, J _2,4) 1.2, J _3,4) 5.7,

J _3,5) 1.3, J _4,5) 2.4, J _5,6a) 11.6,

J _5,6e) 5.1, J _6a,e) 14.1

1.37 (s, 3H), 1.38 (s, 3H), 1.45 (s, 9H), 2.12 (m, 1H),

2.23 (m, 1H), 3.94 (m, 1H), 4.32 (dd, 1H),

4.59 (m, 1H), 4.98 (bd, 1H),

5.65 (m, 1H), 5.77 (m, 1H)

36

A (probe)^c1.37 (s, 3H), 1.43 (s, 3H), 1.44 (s, 9H), 1.95 (ddd, 1H),

2.24 (ddd, 1H), 2.98 (dt, 1H), 3.29 (m, 1H),

1 T 2, 1 T 6a,

1 T 6e, 2 T 3,

3 T 5, 4 T 5,

5 T 6a, 5 T 6e,

6a T 6e

1 T 6e, 1 T 3,

1 T 5, 2 T 6a,

3 T 4, 4 T 5,

5 T 6e, 6a T 6e

1 T 2, 1 T 3 (?),

1 T 5, 2 T 3,

2 T 5 (?), 3 T 4,

4 T 5

4.09 (bm, 1H), 4.19 (dt, 1H), 4.47 (d, 1H)

37

38

40

A (315)

A (325)^h

B (335)

1.32 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.60 (q, 1H),

2.23 (m, 1H), 2.86 (ddd, 1H), 3.41 (dd, 1H),

3.92 (bm, 1H), 3.97 (dd, 1H), 4.24 (t, 1H),

7.25-7.36 (m, 3H), 7.57-7.60 (m, 2H)

J _1,2) 11.3, J _1,6a) 12.8, J _1,6e) 3.1,

J _2,3) 7.1, J _3,4) 5.0, J _4,5) 3.8,

J _5,6a≈ 12.6, J _6a,e≈ 12.9

1.33 (s, 3H), 1.35 (s, 3H), 1.46 (s, 9H), 4.24 (dd, 1H),

4.40 (ddd, 1H), 4.55 (m, 2H), 5.11 (bs, 1H),

5.83 (ddd, 1H), 6.02 (m, 2H)

J _1,2) 9.9, J _1,5) 1.5, J _1,6) 2.3,

J _2,3) 5.3, J _2,4) 0.9, J _2,6) 2.5,

J _3,4) 2.7, J _4,5) 6.8, J _5,6) 4.4

1.36 (s, 9H), 1.83 (dd, 1H), 2.03 (ddd, 1H), 3.17 (ddd, 1H),

3.23 (t, 1H), 3.42 (bm, 1H), 3.60 (bm, 1H), 3.90 (dd, 1H)

J _1,2) 4.0, J _1,6a) 0.9, J _1,6e) 4.8,

J _2,3) 2.2, J _2,4) 1.5, J _3,4) 4.4,

J _4,5) 2.0 J _4,6ee 0.7, J _5,6a) 10.2,

J _5,6e) 6.8, J _6a,e) 15.3

1 T 2, 1 T 6e,

2 T 3, 3 T 4,

3 T 5, 4 T 5,

5 T 6a, 5 T 6e,

6a T 6e

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3241

Ta ble 2 (Con tin u ed )

solvent^a

(T, K)

compd no.

δ (ppm)

J _Values(Hz)

NOE’s

41b

B (350)ⁱ

1.39 (s, 9H), 1.82 (ddd, 1H), 1.89 (s, 3H), 1.97 (s, 3H),

2.02 (s, 3H), 2.23 (ddd, 1H), 3.85 (sex, 1H), 4.00 (m, 1H),

5.03 (dd, 1H), 5.11 (t, 1H), 5.34 (t, 1H), 6.34 (bd, 1H),

7.32 (m, 3H), 7.57 (m, 2H)

J _1,2) 7.7, J _1,6a) 8.7, J _1,6e) 4.0,

J _2,3) 3.2, J _3,4) 2.3, J _4,5) 3.5,

J _5,6a) 7.6, J _5,6e) 3.8, J _6a,e) 14.2

1 T 2, 1 T 6a,

2 T 3, 3 T 4,

3 T 5, 4 T 5,

6a T 6e

42

B (350)

B (380)

1.40 (s, 9H), 1.99 (s, 3H), 2.00 (s, 6H), 4.41 (bm, 1H),

J _1,2) 10.2, J _1,3) 1.4, J _1,6) 3.0,

J _2,3) 3.2, J _2,6) 2.0, J _3,4) 2.1,

J _4,5) 2.1, J _5,6) 2.1

1 T 2, 1 T 3,

1 T 6, 2 T 3,

2 T 6, 3 T 4,

5 T 6

1 T 2, 1 T 3,

1 T 6, 2 T 3,

2 T 4, 3 T 4,

3 T 5, 4 T 5,

5 T 6

5.23 (q, 1H), 5.47 (m, 1H), 5.71 (ddd, 1H), 5.79 (ddd, 1H)

43a

3.75 (bt, 1H), 2.09 (dd, 1H), 3.96 (m, 1H), 4.15 (dt, 1H),

5.79 (ddd, 1H), 5.90 (dddd, 1H)

J _1,2) 10.2, J _1,3) 1.8, J _1,6) 4.1,

J _2,3) 2.3, J _2,4) 1.2, J _2,6) 1.5,

J _3,4) 4.1, J _4,5) 1.8, J _5,6) 5.1

43b

A (330)

1.98 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.11 (s, 3H),

4.98 (bm, 1H), 5.23 (dd, 1H), 5.49 (m, 1H), 5.54 (dt, 1H),

5.71 (m, 1H), 5.86 (ddd, 1H)

J _1,2) 10.1, J _1,3) 3.0, J _1,6) 4.0,

J _2,3) 2.6, J _2,4) 1.1, J _2,6) 0.9,

J _3,4) 4.4, J _4,5) 1.9, J _5,6) 5.6

1 T 2, 1 T 6,

2 T 3, 3 T 5,

4 T 5, 5 T 6

a

b

A ) CDCl₃, B ) DMSO-d₆. Identical J values for spectrum measured at probe temperature. ^cSingle rotamer at probe temperature.

Nonchair conformation with H-6e at δ 2.05 and H-6a at δ 2.40. ^eHalf chair conformation with OH or OAc groups axial. ^fTwisted chair

or boat conformation with NHBoc axial. Chair conformation with PhSe equatorial. Twisted half chair or boat conformation. Note, J _3,4

and J _4,5

d

g

h

i

.

Boat conformation with NHBoc equatorial and 2-OAc axial.

Sch em e 5^a

a

Reagents and conditions: (a) MCPBA/CH₂Cl₂; (b) H₂O, H₂SO₄/THF/70 °C; (c) 6% Na, Hg/Na₂HPO₄/MeOH, THF/-23 °C; (d) Ac₂O/Py;

(e) MCPBA/NaHCO₃/CH₂Cl₂/45 °C; (f) (PhSe)₂/n-BuLi/THF; (g) H₂O₂/(i-Pr)₂NEt/CH₂Cl₂, THF/50 °C; (h) 10% HCl/THF/reflux; (i) NH₃/

MeOH; (j) Ac₂O/Py, cat. 4-DMAP.

C-1, was best prepared from 16 by conversion into the

diol 18 (previously also obtained as one of the products

of peracid oxidation of 15; see Scheme 4), reductive

desulfonylation to 35a with sodium amalgam, and re-

protection. Compound 35b was then converted into (()-

conduramine C-1 (39a ) and the tetraacetyl derivative 39b

by a procedure analogous to that described for (()-

conduramine A-1 and F-1. The melting points and

spectroscopic properties of 39a and 39b were concordant

with those reported in the literature^8e,ffor these sub-

stances.

2. (()-Con d u r a m in e D-1 (Sch em e 7). This previ-

ously unknown conduramine was prepared from the

unprotected cis-diol 35a . (Note the arbitrary change of

the absolute configuration of 35a to correspond to the

absolute configuration of (+)-43a . See also Scheme 8.)

m-Chloroperoxybenzoic acid oxidation of 35a gave the

epoxide 40 with five contiguous cis substitutents exclu-

sively, as expected for peracid epoxidation of cyclic allylic

alcohols.^24,25The transformation of 40 into (()-condu-

ramine D-1 (43a , oily HCl salt) and its crystalline

tetraacetyl derivative 43b was then effected by method-

ology similar to that used for the generation of several

other conduramines. The small values of the H-H

coupling constants (Table 2) for the tetrahedral carbons

of conduramine D-1 and of its tetraacetyl derivative are

fully consistent with the all-cis configuration of these

compounds.

E. Gen er a tion of th e En a n tiom er s of Aza bicy-

cloh ep ta n e 3c (Sch em e 8). A most desirable route for

the preparation of the enantiomers of 3c would require

the use of optically pure catalysts which could then be

used to effect a catalytic, highly enantioselective, Diels-

Alder reaction. Although this specific type of asymmetric

cycloaddition is now known for propargylic aldehydes,²⁶

given the relatively vigorous conditions required to

produce 3c and its derivatives, we opted to study the

preparation of the enantiomers by classical methodology.

The facility with which conjugate additions to the un-

saturated sulfone moiety in 3c and its derivatives took

place (Schemes 2 and 3) induced us to examine the base

catalyzed reaction of 3c with various optically pure

(25) Berti, G. Top. Stereochem. 1973, 7, 93 (See especially pp 130-

152).

(26) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H. J . Org.

Chem. 1997, 62, 3026.

3242 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

Sch em e 6^a

a

Reagents and conditions: (a) MeOH/cat. TsOH; (b) 6% Na, Hg/Na₂HPO₄/MeOH, THF/-23 °C; (c) Me₂C(OMe)₂, Me₂CO/cat. TsOH; (d)

MCPBA/NaHCO₃/CH₂Cl₂; (e) (PhSe)₂/n-BuLi/THF; (f) H₂O₂/(i-Pr)₂NEt/CH₂Cl₂/0 °C, then THF/∆; (g) TFA, H₂/CH₂Cl₂; (h) NH₃/MeOH; (i)

Ac₂O/Py, cat. 4-DMAP.

Sch em e 7^a

a

Reagents and conditions: (a) MCPBA/NaHCO₃/CH₂Cl₂; (b) (PhSe)₂/n-BuLi/THF; (c) Ac₂O/Py, cat. 4-DMAP; (d) H₂O₂/(i-Pr)₂NEt/CH₂Cl₂/0

°C, then THF/∆; (e) 5 N HCl/reflux.

alcohols and amines. Adduct formation took place ef-

ficiently, with high exo selectivity, and in some cases the

diastereomeric mixtures were separable. The most spec-

tacularly successful example was the mixture obtained

from inexpensive (-)(S)-methyl lactate (96% yield). Frac-

tional crystallization of the mixture from hexanes-ethyl

acetate (4:1) gave more and less soluble Michael adducts

44a and 45a , respectively (Scheme 8), each in nearly

theoretical yield. Unfortunately, of all the reaction

conditions studied,²⁷only excess methylmagnesium bro-

mide effected the conversion of the lactate adducts to

enantiopure 3c, albeit in poor yield (e25%). As a

consequence, a modified strategy was devised to regener-

ate the enantiomers of 3c from 44a and 45a . Saponifica-

tion of these esters on one hand and sodium trimethox-

yborohydride reduction²⁸on the other produced the

carboxylic acids 44b and 45b and the primary alcohols

46 and 47. It was hoped that, upon reaction with

n-butyllithium, frank salt formation as well as chelation

of Li⁺with the ethereal oxygen atom would facilitate

anionic â-elimination. Addition of 2.5 equiv of n-butyl-

lithium to a THF solution of either the carboxylic acids

or the alcohols (-78 to -30 °C) caused the rapid appear-

ance of 3c, as judged by TLC. Quenching of these

reaction mixtures and subsequent column chromato-

graphic separation of the products produced enantio-

merically pure (by chiral HPLC) (-)-3c from 44b or 46

and (+)-3c from 45b or 47. These reactions could never,

however, be forced to completion, and the yield of (-)- or

(+)-3c never exceeded 60%, the remainder of the product

being starting material. The inclusion of additives such

as LiCl, SnCl₄, TiCl₄, (i-PrO)₃TiCl, (i-PrO)₄Ti, (i-PrO)₃B,

and so forth in the above reaction mixtures did little to

improve the situation. It was found, however, that the

addition of incremental amounts (up to 2 equiv) of

methylmagnesium bromide (THF) to the n-butyllithium

reaction mixtures at room temperature caused rapid and

complete consumption of the starting material. Then (-)-

or (+)-3c were isolable in >80% yields from both the acids

and the alcohols. In fact, n-butyllithium was not re-

quired; addition of 2.5 equiv of methylmagnesium bro-

mide to THF solutions of 44b or 46 and 45b or 47

routinely produced (-)-3c and (+)-3c in yields exceeding

90%. In this way, the pure enantiomers (-)-3c and (+)-

3c can be produced in 81-85% and 84-87% overall yields

from (()-3c via the carboxylic acid and alcohol routes,

respectively.

F . Absolu te Con figu r a tion of (-)- a n d (+)-3c.

Syn th esis of (-)-Con d u r a m in e C-1 a n d (+)-Con d u -

r a m in e (D-1). With (-)- and (+)-3c now available in

quantity, it was a simple matter to determine their

absolute stereochemistry. Since the absolute configura-

tion of (-)- and (+)-conduramine C-1 has been

established,^8e,fwe chose to find out which of these

enantiomers would be obtained from (-)-3c. Therefore

(-)-3c was converted into the bicyclic acetonide (-)-8

(Scheme 2) which was transformed into the monocyclic

(27) Conditions which did not effect the reverse Michael reaction

were (a) ∆/DMF, (b) Ac₂O/Py-DBU, (c) DBU/THF-reflux, (d) NaH/

DMSO/70 °C, (e) KOtBu/THF-DMF/-78 °C, rt. (f) LDA-THF/-78

°C, rt. (g) n-BuLi-THF/-78 °C, rt.

(28) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem.

Soc. J pn. 1984, 57, 1948.

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3243

Sch em e 8^a

a

Reagents and conditions: (a) (-)-Methyl lactate/cat. NaH/THF, then fractional crystallization; (b) NaOH, MeOH, THF; (c) NaBH₄,

MeOH/THF 70 °C; (d) 2.5 MeMgBr/THF.

acetonide (-)-16 (Scheme 3), and this compound, when

subjected to the sequence of reactions depicted in Scheme

6, gave rise to (-)-conduramine C-1 [(-)-39a , Scheme 8].

Therefore, (-)-3c and (+)-3c must have the absolute

configurations shown in Scheme 8. In addition, (+)-3c

led to (+)-8 and (+)-16, and the latter compound was

converted into (+)-conduramine D-1 by the reaction

sequence shown in Scheme 7. This fixes the absolute

configuration of (+)-conduramine D-1 as 43a (Scheme 8).

strategy, anionic fragmentation of the bicyclic system is

effected before installation of the hydroxyl groups. Thus,

fragmentation of the exo-endo mixture of azabicyclo-

heptenes 11 and 12 efficiently produced the aminocyclo-

hexadiene derivative 15 (Scheme 3) which was then

transformed into (()-tetraacetyl conduramine A-1 (27b,

Scheme 4) and (()-tetraacetyl conduramine F-1 (34b,

Scheme 5).

Racemic 3c was easily separated into enantiopure (-)-

3c and (+)-3c via a process which involved fractional

crystallization of the diastereomeric Michael adducts (-)-

44a and (-)-45a prepared from (-)-methyl lactate (Scheme

8). Saponification or sodium trimethoxyborohydride

reduction of (-)-44a produced (+)-44b or (+)-46, respec-

tively. Reaction of either (+)-44b or (+)-46 with excess

methylmagnesium bromide generated optically pure (-)-

3c in ca. 40% overall yield from racemic 3c. Similarly,

(-)-45a was transformed into (+)-3c via (-)-45b or (-)-

47 with comparable efficiency. Then (-)-3c and (+)-3c

were converted into (-)-conduramine C-1 [(-)-39a ] and

(+)-conduramine D-1 [(+)-43a ] (Scheme 8) by procedures

which had previously been used for the synthesis of the

corresponding racemates.

Con clu sion

The general methodological principles have been worked

out for the conversion of the Boc-pyrrole-derived Diels-

Alder adduct 3c into racemic and optically pure condu-

ramines. Two general strategies were devised for this

purpose. One of these involves the regio- and stereose-

lective hydroxylation of 3c to compounds such as 10b

(Scheme 2) and the exo-endo mixture 13-14 (Scheme

3), and subsequent anionic fragmenation (methylmag-

nesium bromide or lithium bis(trimethylsilylamide) to the

highly functionalized cyclohexene derivatives 17 and 16,

respectively (Scheme 3). Compound 17 is an aminocy-

clitol with the stereochemistry of a conduramine C but

with an altered substituent sequence. Compound 16

served as a precursor of (()-conduramine C-1 (39a ,

Scheme 6) and the previously unknown, all-cis-(()-

conduramine D-1 (43a ) (Scheme 7). In the second

It is quite probable that the methodology disclosed

herein could be applied to prepare any imaginable

conduramine derivative in both the racemic and optically

pure forms. In addition, the ready availability of (-)-

and (+)-3c makes them attractive starting materials for

3244 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

The enantiomers could be separated by HPLC on a Chiracel

OD-H column using hexanes-ethyl acetate (9:1), a flow rate

of 0.8 mL/min and scanning at 230 nm. Two equiintense peaks

at 22.3 and 25.2 min corresponding to (+)- and (-)-3c,

respectively, were observed (see below).

the synthesis of a number of natural products. The

results of studies along these lines will be disclosed in

due course.

Exp er im en ta l Section

(()-2-p-Tolu en esu lfon yl-7-eth oxycar bon yl-7-azabicyclo-

[2.2.1]h ep ta d ien e (3b): obtained in 75% yield as an oil; MS

m/z (rel intensity) 319 (M⁺, 8), 164 (25), 139 (100), 92 (19), 91

(18), 67 (19). Anal. Calcd for C₁₆H₁₇NO₄S: C, 60.17; H, 5.37;

N, 4.39. Found: C, 60.36; H, 5.05; N, 4.18.

(()-2-p-Tolu en esu lfon yl-7-(-)-m en th yloxyca r bon yl-7-

a za bicyclo[2.2.1] h ep ta d ien e (3d ): obtained in 75% yield

as a foam; MS m/z (rel intensity) 429 (M⁺, 5), 292 (14), 274

(12), 249 (30), 233 (24), 182 (18), 155 (17), 138 (45), 136 (21),

97 (25), 92 (33), 91 (50), 83 (100), 67 (44), 57 (47). Anal. Calcd

for C₂₄H₃₁NO₄S: C, 67.10; H, 7.27; N, 3.26. Found: C, 66.89;

H, 7.50; N, 3.21.

The terms “worked up in the usual manner”, “the usual

workup”, and so forth signify that the organic phase was

washed with saturated aqueous NaCl solution and then dried

over anhydrous MgSO₄or NaSO₄after which the solvent was

removed in vacuo. Unless stipulated otherwise, the terms

“column chromatography” and “column chromatographic pu-

rification” signify purification by flash column chromatography

on silica gel.

IR spectra were recorded as dispersions in KBr unless

specified otherwise. NMR spectra (300 MHz) were measured

in CDCl₃solution at the probe temperature unless indicated

otherwise.

(-)-1-Men th yloxyca r bon ylp yr r ole (1d ). A. P yr r olyl-

sod iu m . A solution of pyrrole (2.8 mL, 2.7 g, 40 mmol) in

anhydrous THF (80 mL) was added to a stirred suspension of

sodium hydride (1.6 g, 60% suspension in mineral oil, 40 mmol)

(N₂atmosphere) in anhydrous THF (20 mL), and then the

mixture was stirred at reflux temperature for 3 h.

B. (-)-Men th yl ch lor ofor m a te. Solutions of pyridine (3.3

mL, 3.2 g, 40 mmol) in dry dichloromethane (50 mL) and (-)-

menthol (6.24 g, 40 mmol) in dry dichloromethane (50 mL)

were added sequentially to a stirred and cooled (0 °C) solution

of phosgene in toluene (23.3 mL of a 1.93 M solution, 45 mmol).

Stirring at 0 °C was continued for 2 h, the mixture was filtered,

and the filtrate was evaporated in vacuo to give the chloro-

formate as an oil.

To prepare compound 1d , a solution of the above chlorofor-

mate in anhydrous THF (20 mL) was added to the stirred

suspension of the above pyrrolylsodium cooled to 0 °C. The

mixture was stirred at this temperature for 3 h, excess dilute

aqueous NH₄Cl and ethyl acetate were added sequentially, and

this was followed by the usual workup procedures. The crude

product was purified by column chromatography, using hexane

to elute pure 1d as an oil (7.9 g, 79% yield): IR (neat) 1744

cm^-1; ¹H NMR δ 0.81 (3H, d, J ) 7.0 Hz), 0.92 (d, 2H, J ) 7.0

Hz), 0.93 (d, 2H, J ) 7.0 Hz), 1.10-1.19 (m, 2H), 1.47-1.60

(m, 2H), 1.68-1.77 (m, 2H), 1.95 (sept, 0.5H, J ) 7.0 Hz), 1.96

(sept, 0.5H, J ) 7.0 Hz), 2.13-2.20 (m, 1H), 4.83 (dt, 1H, J )

4.4, 10.9 Hz), 6.23 (t, 2H), 7.27 (t, 2H); MS m/z (relative

intensity) 249 (M⁺, 5). Anal. Calcd for C₁₅H₂₃NO₂: C, 72.25;

H, 9.30; N, 5.62. Found: C, 72.29; H, 9.43; N, 5.53. [R]_D

-100.0° (c 0.121, CHCl₃).

(()-2-p-Tolu en esu lfon yl-5-exo-6-exo-d ih yd r oxy-7-ter t-

bu toxyca r bon yl-7-a za bicyclo[2.2.1]h ep t-2-en e (7). A. Di-

r ect P r ocess. Solutions of compound 3c (13.9 g, 40 mmol)

in THF (50 mL), N-methylmorpholine-N-oxide (7.0 g, 60

mmol), and osmium tetroxide (4 mL of a 2.5 wt % solution in

tert-butyl alcohol) were added in succession to a stirred solution

of sodium bicarbonate (3.36 g, 40 mmol) in tert-butyl alcohol

(320 mL) and water (80 mL). The reaction mixture was stirred

at room temperature for 16 h (complete by TLC after 5 h),

and then excess 10% aqueous NaHSO₃solution was added.

Stirring was continued for 30-45 min, and then the reaction

mixture was diluted with a large volume of ethyl acetate and

worked up in the usual manner. Compound 7 was isolated

from the crude reaction product by column chromatography

on silica gel, using hexanes-ethyl acetate (7:3) and then

dichloromethane-methanol (98:2) to elute the solid product.

Recrystallization of this material from hexanes-ethyl acetate

gave 7 as a solid (11.5 g, 73%): mp 168-170 °C; IR 3443, 1713,

1688, 1590, 1387, 1317 cm^-1

. Anal. Calcd for C₁₃H₂₃NO₆S:

C, 56.68; H, 6.08; N, 3.67. Found: C, 56.71; H, 6.26; N, 3.18.

(-)-2-p-Tolu en esu lfon yl-5-exo,6-exo-d ih yd r oxy-7-ter t-

bu toxycar bon yl-7-azabicyclo[2.2.1]h ept-2-en e [(-)-7]. This

compound was prepared by the method used for (()-7 except

that the reaction time was 2.5 h. Pure (-)-7 was obtained in

89% yield: mp 152-153 °C; ¹³C NMR (DMSO-d₆+ CDCl₃; 360

K) δ 21.42, 27.80 (3C), 66.92, 67.64, 68.27, 80.81, 128.02 (2C),

129.71 (2C), 136.44, 143.59, 145.03, 150.35, 155.98. Anal.

Calcd for C₁₈H₂₃NO₆S: C, 56.68; H, 6.08; N, 3.67. Found: C,

56.78; H, 6.23; N, 3.76. [R]_D-24.7° (c 0.2185, CHCl₃).

(+)-2-p-Tolu en esu lfon yl-5-exo,6-exo-d ih yd r oxy-7-ter t-

bu toxycar bon yl-7-azabicyclo[2.2.1]h ept-2-en e [(+)-7]. This

compound was prepared by the method used for (()-7, except

that the reaction time was 6 h. Pure (+)-7, obtained in 84%

yield after crystallization from ethyl acetate-hexane, had mp

150-151 °C. Anal. Calcd for C₁₈H₂₃NO₆S: C, 56.68; H, 6.08;

N, 3.67. Found: C, 56.53; H, 6.18; N, 3.67. [R]_D+23.3° (c

0.245, CHCl₃).

Syn th esis of th e 2-Ar ylsu lfon yl-7-a lk oxyca r bon yl-7-

a za bicyclo[2.2.1]h ep ta d ien es (3). (()-2-p-Tolu en esu lfo-

n y l -7 -t e r t -b u t o x y c a r b o n y l -7 -a z a b i c y c l o [ 2 .2 .1 ] -

h ep ta d ien e (3c). The synthesis of this compound was typical.

A mixture of 1-tert-butoxycarbonylpyrrole (1c)²⁹(33.4 g, 0.2

mol) and ethynyl p-tolyl sulfone³⁰(2a ) (18.0 g, 0.1 mol) was

heated in an inert atmosphere at 80-85 °C for 48 h. The

reaction mixture was separated into its components by column

chromatography. Elution with hexanes-ethyl acetate (95:5)

gave recovered 1c (16.5 g), and a small amount of 2a (0.2 g)

was eluted with hexanes-ethyl acetate (9:1). The product was

eluted with hexanes-ethyl acetate (4:1) as a solid which on

crystallization from hexanes-ethyl acetate gave pure 3c (29.5

g, 84% yield), mp 97-98 °C. A reaction carried out on triple

this scale gave pure 3c in 82% yield: IR 1707, 1595, 1372,

B. Via P h en yl Bor on ic Acid Ester 6. A solution of 3c

(19.0 g, 55 mmol) was added to a stirred mixture of dichlo-

romethane (150 mL), osmium tetroxide (18 mL of a 2.5 wt %

solution in tert-butyl alcohol), N-methylmorpholine N-oxide

(8.4 g, 71.5 mmol), and phenylboronic acid (8.72 g, 71.5 mmol).

After 24 h, a 10% NaHSO₃solution was added, and after 1 h,

the mixture was filtered through Celite. The filtrate was

concentrated in vacuo, and the phenyl boronate 6 was isolated

from the residue by column chromatography, using dichlo-

romethane-ethyl acetate (9:1) to elute the solid product (24.3

g). Crystallization of this material from dichloromethane-

ethyl acetate gave pure 6 (23.6 g, 92% yield): mp 197-200

1345, 1316, 1152 cm^-^{1 13}C NMR (DMSO-d₆; 340 K) δ 20.98,

;

27.54 (3C), 66.49, 67.86, 80.46, 127.57 (2C), 130.13 (2C),

135.64, 141.72 (2C), 142.78, 144.72, 153.12, 158.25; MS m/z

(rel intensity) 347 (M⁺, 2), 291 (6), 182 (18), 92 (23), 91 (24),

67 (51), 57 (100). Anal. Calcd for C₁₈H₂₁NO₄S: C, 62.23; H,

6.09; N, 4.03. Found: C, 62.25; H, 5.91; N, 4.27.

°C; IR 1709, 1372, 1325, 1157 cm^-^{1 13}C NMR δ 21.70, 27.66

;

(3C), 65.48, 66.78, 79.2, 80.10, 81.57, 127.85, 128.71, 130.32,

131.82, 135.00, 135.9, 143.8, 145.58; MS m/z (rel intensity) 467

(M⁺, 4). Anal. Calcd for C₂₄H₂₆BNO₆S: C, 61.68; H, 5.61; N,

3.00. Found: C, 61.76; H, 6.01; N, 3.16.

Aqueous hydrogen peroxide (30%, 50 mL) was added to a

stirred solution of the above boronate (20.1 g, 43 mmol) in THF

(200 mL) and dichloromethane (300 mL) at room temperature.

(29) Grehn, L.; Ragnarsson, V. Angew. Chem., Int. Ed. Engl. 1984,

23, 296.

(30) Chen, Z.; Trudell, M. L. Synth. Commun. 1994, 24, 3149.

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3245

After 1 h, water (250 mL) was added, and 0.5 h later the

organic phase was separated and washed with 10% aqueous

NaHSO₃solution. After the usual workup, the crude product

was purified by flash column chromatography on neutral

alumina (Act II), using dichloromethane and then dichlo-

romethane-methanol (9:1) to elute the pure crystalline diol 7

(14.5 g, 88% yield).

Aceton id e of (()-2-p-Tolu en esu lfon yl-5-exo,6-exo-d i-

h yd r oxy-7-ter t-bu toxyca r bon yl-7-a za bicyclo[2.2.1]h ep t-

2-en e (8). A solution of the diol 7 (18.0 g, 47.2 mmol) in

acetone (75 mL) and 2,2-dimethoxypropane (75 mL) containing

p-toluenesulfonic acid monohydrate (0.5 g) was stirred at room

temperature for 3 h. The solution was made neutral with a

few drops of triethylamine, and then the volatile materials

were removed in vacuo. The residue was dissolved in ethyl

acetate and washed with dilute HCl solution, and the organic

phase was worked up in the usual way.

acid (1.9 mL, 2.85 g, 25 mmol) in THF (5 mL) was added to a

stirred suspension of sodium borohydride (0.95 g, 25 mmol)

in THF (75 mL) at room temperature. When gas evolution

had ceased, a solution of the oximate 10a (1.7 g, 3.1 mmol) in

THF (25 mL) was added, and the reaction mixture was stirred

for 2 h at room temperature, followed by stirring for 2 h at

reflux temperature. Dilute hydrochloric acid was added to the

reaction mixture at room temperature, and then it was

evaporated to dryness in vacuo. Dichloromethane was added

to the residue and the organic phase was washed successively

with dilute NH₄Cl solution and saturated NaCl solution and

then was dried (MgSO₄). The solvent was evaporated in vacuo,

and the residue was subjected to column chromatographic

purification. Elution with hexanes-ethyl acetate mixtures

(4:1 and then 1:1) gave the endo-hydroxy compound 10b as a

solid (1.15 g, 85% yield): mp 208-209 °C (ethyl acetate-

hexane); IR (KBr) 3434, 1707, 1676, 1152 cm^-1. Anal. Calcd

for C₂₁H₂₉NO₇S: C, 57.39; H, 6.65; N, 3.19. Found: C, 57.38;

H, 6.72; N, 3.36.

The residue was crystallized from ethyl acetate to give a

solid (16.9 g, 85% yield): mp 121-122 °C; IR 1717, 1370, 1354,

1318, 1152 cm^-^{1 13}C NMR (320 K) δ 21.68, 25.62, 26.23, 27.82

;

(()-2-exo- a n d (()-2-en d o-p-Tolu en esu lfon yl-7-ter t-bu -

toxyca r bon yl-7-a za bicyclo[2.2.1]h ep t-5-en e (11 a n d 12).

A mixture of the diene 3c (1.39 g, 4 mmol) and sodium

borohydride (1.20 g, 32 mmol) in methanol (80 mL) was stirred

at room temperature for 3 h. The reaction mixture was made

acidic with dilute HCl solution, the volatile materials were

removed in vacuo, and ethyl acetate was added to the residue.

After the usual workup the product mixture was separated

into its components by column chromatography, using hex-

anes-ethyl acetate mixtures (4:1 and then 1:1) to elute the

less polar endo-sulfone 12 and then the exo-sulfone 11.

Crystallization of the exo isomer from dichloromethane-

pentane gave pure 11 (0.12 g, 9%): mp 95-96 °C; IR 1715,

(3C), 64.25, 65.18, 78.90, 79.80, 80.86, 116.69, 128.16, 130.29,

135.8, 144.37, 145.41, 150.8, 155.1; MS m/z (CI/NH₃) (rel

intensity) 439 (MH⁺, 4), 383 (4), 322 (23), 299 (23), 297 (71),

280 (100), 161 (46). Anal. Calcd for C₂₁H₂₇NO₆S: C, 59.84;

H, 6.46; N, 3.32. Found: C, 59.99; H, 6.42; N, 3.27.

If this acetonide was prepared without purification of the

crude dihydroxy compound 7 (prepared by method a), the yield

of 8 was 83%.

Aceton id e of (-)-2-p-Tolu en esu lfon yl-5-exo,6-exo-d i-

h y d r o x y -7-t er t -b u t o x y c a r b o n y l-7-a za b ic y c lo [2.2.1]-

h ep ten e-2-en e [(-)-8]. This compound was prepared in 97%

yield by the method used for (()-8, except that the reaction

time was 0.5 h, and the pure compound was obtained by

column chromatography, using hexanes-ethyl acetate (4:1) as

the eluant. Pure (-)-8 had mp 148-149 °C. Anal. Calcd for

1370, 1165, 1150 cm^-^{1 13}C NMR (DMSO-d₆, 330 K) δ 20.65,

;

27.25, 27.55 (3C), 58.82, 60.72, 62.74, 79.09, 127.05, 128.22

(2C), 129.38 (2C), 129.69, 135.26, 143.94, 152.61. Anal. Calcd

for C₁₈H₂₃NO₄S: C, 61.87; H, 6.63; N, 4.01. Found: C, 61.63;

H, 6.55; N, 3.88. Crystallization of the endo isomer from

hexanes-ethyl acetate gave pure 12 (1.20 g, 86%): mp 101-

C

₂₁H₂₇NO₆S: C, 59.84; H, 6.46; N, 3.32. Found: C, 60.12; H,

6.53; N, 3.45. [R]_D-15.5° (c 1.1175, CHCl₃).

Aceton id e of (+)-2-p-Tolu en esu lfon yl-5-exo,6-exo-d i-

h ydr oxy-7-ter t-bu toxycar bon yl-7-azabicyclo[2.2.1]h epten -

2-en e [(+)-8]. This compound was prepared by the method

used for (()-8. Pure (+)-8 was obtained in 96% yield after

column chromatography [hexanes-ethyl acetate mixtures (9:1

and then 4:1)] and crystallization from hexanes-ethyl acetate.

It had mp 119-120 °C. Anal. Calcd for C₂₁H₂₇NO₆S: C, 59.84;

H, 6.46; N, 3.32. Found: C, 59.76; H, 6.63; N, 3.47. [R]_D

+15.3° (c 1.06, CHCl₃).

102 °C; IR 1717, 1370, 1350, 1150 cm^-^{1 13}C NMR (DMSO-d₆,

;

330 K) δ 20.74, 27.46 (3C), 28.25, 60.50 (2C), 61.30, 79.74,

127.15, 127.42 (2C), 129.70 (2C), 131.00, 136.65, 144.19,

153.20. Anal. Calcd for C₁₈H₂₃NO₄S: C, 61.87; H, 6.63; N,

4.01. Found: C, 62.09; H. 6.60; N, 4.22.

Both 11 and 12 readily undergo fragmentation to 1-tert-

butoxycarbonylpyrrole and p-toluenesulfonylethylene at ca. 60

°C.

Aceton id es of (()-2-exo- a n d (()-2-en d o-p-Tolu en e-

su lfon yl-5-exo,6-exo-d ih yd r oxy-7-ter t-bu toxyca r bon yl-7-

a za bicyclo[2.2.1]h ep ta n e (13 a n d 14). A mixture of com-

pound 8 (8.4 g, 20 mmol) and sodium borohydride (6.1 g, 160

mmol) in methanol (300 mL) was stirred at 0 °C for 2 h, and

then the reaction mixture was worked up as above for 11 and

12. The crude product was separated into its components by

column chromatography exactly as described for 11 and 12.

The endo isomer 14 (0.80 g, 9%) was eluted first. The major,

more polar, exo isomer 13 (7.62 g, 90%): mp 169-171 °C (ethyl

acetate-hexane); IR 1701, 1368, 1152 cm^-1; MS m/e (CI/NH₃)

(rel intensity) 441 [(MNH₄)⁺, 20], 384 (100), 324 (44), 168 (33).

Anal. Calcd for C₂₁H₂₉NO₆S: C, 59.55; H, 6.90; N, 3.31.

Found: C, 59.83; H, 6.66; N, 2.98. The endo isomer 14: mp

Syn t h esis of Ben za ld oxim e Ad d u ct s (()-9a a n d (()-

10a fr om (()-8. A solution of sodium methylsulfinylmethide

in DMSO (3 mL of a 0.1 M solution, 0.3 mmol) was added to

a stirred solution of benzaldoxime (0.36 g, 3 mmol) in anhy-

drous DMSO (40 mL), and this solution was heated at 70 °C

for 0.5 h. To this solution, at room temperature, was added a

solution of 8 (1.26 g, 3 mmol) in dry DMSO (15 mL), and the

resulting solution was stirred at room temperature for 16 h.

The solution was poured onto ice, acidified with dilute HCl,

and extracted with ethyl acetate. The extract was washed

with a 10% NaOH solution and then worked up in the usual

manner.

The solvent was removed in vacuo, and the residue was

separated into its components by column chromatography,

using hexanes-ethyl acetate mixtures (9:1 and then 85:15)

as eluants. The 2-endo-3-exo compound 9 was eluted first

(0.18 g, 11%), followed by the 2-exo-3-endo adduct 10a (1.34

g, 82%). Compound 9: mp 78-80 °C (hexanes-ethyl acetate);

134-136 °C (ethyl acetate-hexane); IR 1705, 1371, 1146 cm^-1

;

¹³C NMR (CDCl₃) δ 21.33, 24.20, 25.34, 28.05 (3C), 59.64,

59.99, 61.60, 80.74, 81.15, 110.59, 127.62 (2C), 130.15 (2C),

136.06, 145.02, 153.81. Anal. Calcd for C₂₁H₂₉NO₆S: C, 59.55;

H, 6.90; N, 3.31. Found: C, 59.65; H, 6.94; N, 3.46.

IR (KBr) 1705, 1638, 1383, 1152 cm^-1

C

.

Anal. Calcd for

₂₈H₃₄N₂O₇S: C, 61.97; H, 6.32; N, 5.16. Found: C, 61.97; H,

6.55; N, 4.95.

Compound 10a : mp 171 °C (hexanes-ethyl acetate); IR

1709, 1630, 1597, 1392, 1370, 1150 cm^-1

Anal. Calcd for

₂₈H₃₄N₂O₇S: C, 61.97; H, 6.32; N, 5.16. Found: C, 61.92; H,

6.28; N, 5.15.

Aceton id es of (-)-2(S)-exo- a n d (+)-2(R)-en d o-p-Tolu -

en esu lfon yl-5-exo,6-exo-dih ydr oxy-7-ter t-bu toxycar bon yl-

7-a za bicyclo[2.2.1]h ep ta n e [(-)-2(S)-13 a n d (+)-2(R)-14].

These were prepared by the method used for the racemates

except that hexanes-ethyl acetate (4:1) was used as the eluant

for the chromatographic separation of the exo and endo

isomers. The exo compound (-)-2-(S)-13 was obtained in 85%

yield and had mp 179-180 °C. Anal. Calcd for C₂₁H₂₉NO₆S:

C, 59.55; H, 6.90; N, 3.31. Found: C, 59.70; H, 6.97; N, 3.43.

[R]_D-39.8° (c 1.0225, CHCl₃).

.

C

Aceton id e of (()-2-exo-p-Tolu en esu lfon yl-3-en d o-h y-

d r oxy-5-exo,6-exo-d ih yd r oxy-7-ter t-b u t oxyca r b on yl-7-

a za bicyclo[2.2.1]h ep ta n e (10b). A solution of trifluoroacetic

3246 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

The endo compound (+)-2-(R)-14 was isolated in 11% yield

and had mp 134-136 °C. Anal. Calcd for C₂₁H₂₉NO₆S: C,

59.55; H, 6.90; N, 3.31. Found: C, 59.65; H, 6.94; N, 3.46.

[R]_D+20.0° (c 0.545, CHCl₃).

Aceton id es of (+)-2(R)-exo- a n d (-)-2(S)-en d o-p-Tolu -

en esu lfon yl-5-exo,6-exo-dih ydr oxy-7-ter t-bu toxycar bon yl-

7-a za bicyclo[2.2.1]h ep ta n e [(+)-2(R)-13 a n d (-)-2(S)-14].

These compounds were prepared by the method used for the

racemates except that the chromatographic separation was

effected, using hexanes-ethyl acetate mixtures (4:1 and then

1:1) as the eluting solvents. (+)-2(R)-exo-13 was obtained in

88% and had mp 167-169 °C. Anal. Calcd for C₂₁H₂₉NO₆S:

C, 59.55; H, 6.90; N, 3.31. Found: C, 59.81; H, 6.97; N, 3.32.

[R]_D+39.9° (c 1.055, CHCl₃).

being sonicated. A THF-toluene solution of methylmagne-

sium bromide (8.8 mL of a 1.4 M solution, 12.3 mmol) was

added in six equal portions at 5 min intervals to a stirred

solution of 10b (0.90 g, 2.05 mmol) in dry THF (75 mL) under

an argon atmosphere. The reaction mixture was then stirred

for an additional 1.5 h and quenched with dilute HCl solution.

After the usual workup, the crude product was purified by

column chromatography. Elution with hexanes-ethyl acetate

(7:3) gave 17 (0.75 g, 83%), and further elution with 1:1

hexanes-ethyl acetate gave a small amount (0.052 g, 6%) of

the starting material. Compound 17: mp 185 °C (ethyl

acetate-hexane); IR 3441, 1713, 1676, 1597, 1370, 1150 cm^-1

;

¹³C NMR (DMSO-d₆, 350 K) δ 20.97, 25.82, 27.25, 28.02 (3C),

53.54, 63.62, 71.25, 74.45, 109.18, 127.98 (2C), 129.34 (2C),

135.91, 137.65, 142.65, 143.81, 155.15. Anal. Calcd for

The (-)-2(S)-endo-14 was obtained in 9.5% yield and had

mp 129-131 °C. Anal. Calcd for C₂₁H₂₉NO₆S: C, 59.55; H,

6.90; N, 3.31. Found: C, 59.53; H, 7.00; N, 3.25. [R]_D-20.2°

(c 0.535, CHCl₃).

C

₂₁H₂₉NO₇S: C, 57.39; H, 6.65; N, 3.19. Found: C, 57.45; H,

6.73; N, 3.35.

(()-1-p -Tolu en esu lfon yl-cis-3,4-d ih yd r oxy-5-cis-ter t-

bu toxyca r bon yla m in ocycloh exen e (18). A solution of

compound 16 (2.12 g, 5.0 mmol) in methanol (150 mL)

containing p-toluenesulfonic acid monohydrate (0.2 g) was

stirred at room temperature for 6 h. A few drops of triethy-

lamine was added, and the solvent was removed in vacuo. The

residue was dissolved in ethyl acetate, washed with dilute HCl,

and dried, and the solvent was eliminated in vacuo. Crude

18 was purified by column chromatography, using hexanes-

ethyl acetate (4:1), followed by dichloromethane-methanol (99:

1) as the eluant. Compound 18 was obtained as a solid (1.71

g, 89%): mp 189-189.5 °C (ethyl acetate-hexane); IR 3430,

(()-1-p-Tolu en esu lfon yl-5-ter t-bu toxyca r bon yla m in o-

1,3-cycloh exa d ien e (15). A solution of a mixture of the exo-

and endo-sulfones 11 and 12 (13.0 g, 37.5 mmol) in dry THF

(50 mL) was added dropwise to a stirred solution of lithium

bis(trimethylsilyl)amide (56.2 mmol) in THF (450 mL) at -78

°C (inert atmosphere). After the solution was added, the

reaction mixture was left to warm to -20 °C at which

temperature stirring was continued for 45 min. The reaction

mixture was quenched with excess dilute NH₄Cl solution, ethyl

acetate was added, and after the usual workup, the product

was obtained pure by column chromatography. It was eluted

from the column with hexanes-ethyl acetate (4:1), and on

crystallization of the material so obtained from hexanes-ethyl

acetate, 15 was isolated as a white solid (10.4 g, 76%): mp

3373, 1709, 1663, 1534, 1146 cm^-^{1 13}C NMR (DMSO-d₆, 315

;

K) δ 21.64, 26.47, 28.81 (3C), 50.53, 69.33, 70.28, 80.55, 129.26

(2C), 131.08 (2C), 136.98, 138.74, 140.32, 146.27, 157.50. Anal.

Calcd for C₁₈H₂₅NO₆S: C, 56.38; H, 6.57; N, 3.62. Found: C,

56.53; H, 6.72; N, 3.52.

This compound could also be obtained as one component of

the 1:1 mixture produced upon osmate catalyzed cis dihy-

droxylation of the diene 15.

130-132 °C; IR 3428, 3328, 1701, 1676, 1366, 1151 cm^-^{1 13}C

;

NMR (330 K) δ 21.49, 28.01, 28.08 (3C), 42.80, 79.65, 123.85,

127.92, 129.59, 129.82, 131.86, 135.76, 136.20, 144.29, 154.34.

Anal. Calcd for C₁₈H₂₃NO₄S: C, 61.87; H, 6.63; N, 4.01.

Found: C, 61.97; H, 6.70; N, 4.15.

Aceton ide of (()-1-p-Tolu en esu lfon yl-3,4-cis-dih ydr oxy-

5-cis-ter t-bu toxyca r bon yla m in ocycloh exen e (16). A solu-

tion of a mixture of the exo- and endo-sulfones 13 and 14 (6.1

g, 14.4 mmol) in dry THF (50 mL) was added dropwise at -78

°C (inert atmosphere) to a stirred solution of lithium bis-

(trimethylsilyl)amide (21 mmol) in THF (250 mL). The reac-

tion mixture was left to reach room temperature (1 h), and

after an additional hour, it was worked up exactly as described

for the synthesis of 15. After crystallization of the crude

product from hexanes-ethyl acetate, 16 was obtained as a

white solid (4.8 g, 79%): mp 181-182 °C; IR 3437, 3374, 1713,

(+)-1-p -T o lu e n e s u lfo n y l-ci s-3(S ),4(R )-D ih y d r o x y -

5(R)-cis-ter t-b u t oxyca r b on yla m in ocycloh exen e

[(+)-

3(S),4(R),5(R)-18]. This compound was prepared from (-)-

16 by the method used to prepare (()-18 except that the

column chromatographic purification was effected with ethyl

acetate-hexane (4:1) and dichloromethane-methanol (98:2)

as the eluting solvents. Pure (+)-18 was obtained in 95% yield

and had mp 207 °C. Anal. Calcd for C₁₈H₂₅NO₆S: C, 56.38;

H, 6.57; N, 3.62. Found: C, 56.28; H, 6.70; N, 3.45. [R]_D

+39.1° (c 0.2325, CHCl₃). The specific rotation was identical

in methanol solution.

1696, 1522, 1370, 1152 cm^-^{1 13}C NMR δ 21.67, 24.56, 26.47,

;

(-)-1-p -T o lu e n e s u lfo n y l-ci s-3(R ),4(S )-D ih y d r o x y -

27.73, 28.33 (3C), 72.78, 74.44, 80.15, 110.28, 128.30 (2C),

130.02 (2C), 132.76, 135.26, 140.04, 144.87, 155.00. Anal.

Calcd for C₂₁H₂₉NO₆S: C, 59.55; H, 6.90; N, 3.30. Found: C,

59.95; H, 6.69; N, 2.97.

Aceton ide of (-)-1-p-Tolu en esu lfon yl-3,4-cis-dih ydr oxy-

5-cis-ter t-bu toxycar bon ylam in ocycloh exen e [(-)-16]. This

compound was prepared in the manner described for (()-16

except that pure (-)-2(S)-exo-13 was used and hexanes-ethyl

acetate (85:15) was the solvent system utilized in the column

chromatographic purification. Pure (-)-16 was obtained in

5(R)-cis-ter t-b u t oxyca r b on yla m in ocycloh exen e

[(-)-

3(R),4(S),5(R)-18]. This compound was prepared from (+)-

16 in the same manner that was used to obtain the racemate

except that the chromatographic purification was effected with

hexanes-ethyl acetate mixtures (4:1 and then 98:2) as the

eluting solvents. Pure (-)-18 was obtained in 92% yield as a

solid and had mp 188-189 °C. Anal. Calcd for C₁₈H₂₅NO₆S:

C, 56.38; H, 6.57; N, 3.62. Found: C, 56.34; H, 6.65; N, 3.48.

[R]_D-40.0° (c 0.355, CHCl₃).

80% yield and had mp 132-134 °C. Anal. Calcd for C₂₁H₂₉

-

N,N-Bis-ter t-b u t oxy Der iva t ive of (()-1-p -Tolu en e-

su lfon yl-5-a m in ocycloh ex-1,3-d ien e (20). A solution of the

diene 15 (2.1 g, 6 mmol) in acetonitrile (100 mL) containing

di-tert-butyldicarbonate (2.6 g, 12 mmol) and 4-(dimethylami-

no)pyridine (0.250 g) was stirred at room temperature for 16

h. The reaction mixture was diluted with ethyl acetate, and

the resulting solution was washed with dilute aqueous HCl

and then worked up in the usual way. The pure bis-Boc

derivative 20 (2.25 g, 85%) was obtained by column chroma-

tography of the crude product, using hexanes-ethyl acetate

(4:1) as the eluant. Pure 20 had mp 121-122 °C (hexanes-

NO₆S: C, 59.55; H, 6.90; N, 3.31. Found: C, 59.70; H, 6.70;

N, 3.17. [R]_D-26.3° (c 0.6465, CHCl₃).

Aceton ide of (+)-1-p-Tolu en esu lfon yl-3,4-cis-dih ydr oxy-

5-cis-ter t-bu toxycar bon ylam in ocycloh exen e [(+)-16]. This

compound was prepared in the manner used for (()-16 except

that (+)-2(R)-13 was used, and (+)-16 was eluted from the

column with hexanes-ethyl acetate (4:1). After crystallization

from hexanes-ethyl acetate, pure (+)-16 was obtained in 75%

yield and had mp 173-175 °C. Anal. Calcd for C₂₁H₂₉NO₆S:

C, 59.55; H, 6.90; N, 3.31. Found: C, 59.70; H, 6.64; N, 3.39.

[R]_D+25.5° (c 0.710, CHCl₃).

ethyl acetate); IR 1755, 1707, 1370, 1152 cm^-^{1 13}C NMR δ

;

Aceton ide of (()-1-p-Tolu en esu lfon yl-cis-3,4-dih ydr oxy-

cis-5-ter t-b u t oxyca r b on yla m in o-tr a n s-6-h yd r oxycyclo-

h exen e (17). All solutions were degassed by passing a slow

stream of argon through them for 5-10 min while they were

21.61, 25.72, 27.96 (6C), 52.92, 80.30 (2C), 120.18, 128.07 (2C),

129.87 (2C), 130.18, 135.00, 136.31, 136.76, 144.36, 152.01

(2C). Anal. Calcd for C₂₃H₃₁NO₆S: C, 61.45; H, 6.95; N, 3.12.

Found: C, 61.54; H, 7.02; N, 3.21.

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3247

N,N-Bis-ter t-b u t oxyca r b on yl Der iva t ive of (()-1-p -

Tolu en esu lfon yl-3,4-cis-d ih yd r oxy-tr a n s-5-a m in ocyclo-

h exen e (21). Compound 20 was converted into the cis-diol

21 by the same method which was used to convert 3c into 7.

Purification of the crude product by column chromatography,

using hexanes-ethyl acetate mixtures (3:1 and then 1:1),

eluted pure 21 in 91% yield: mp 156-159 °C (ethyl acetate-

hexane); IR 3445, 1740, 1701, 1653, 1647, 1635, 1370, 1152

romethane (5 mL) was added 30% aqueous hydrogen peroxide

(0.1 mL) and diisopropylethylamine (0.1 mL). After 15 min,

THF (5 mL) was added, and the mixture was heated at 50 °C

for 1.5 h. The mixture was cooled to room temperature, ethyl

acetate was added, and the organic phase was washed suc-

cessively with dilute sodium carbonate solution, dilute hydro-

chloric acid, and saturated NaCl solution. The dried organic

phase was evaporated in vacuo, and the residue was subjected

to column chromatographic purification, using hexanes-ethyl

acetate mixtures (4:1 and then 7:3) to elute 26 as a solid (0.023

g, 90% yield): mp 93-95 °C (hexanes-ethyl acetate); IR (neat)

cm^-^{1 13}C NMR δ 21.63, 27.62, 27.79 (6C), 52.93, 65.86, 68.80,

;

83.18 (2C), 128.38 (2C), 130.05 (2C), 133.79, 135.07, 142.81,

144.94, 153.37 (2C). Anal. Calcd for C₂₃H₃₃NO₈S: C, 57.13;

H, 6.88; N, 2.90. Found: C, 57.01; H, 6.93; N, 2.49.

3451, 3406, 1717, 1699, 1501 cm^-^{1 13}C NMR δ 24.79, 27.02,

;

(()-3,4-cis-Dih yd r oxy-5-t r a n s-t er t -b u t oxyca r b on yl-

a m in ocycloh exen e (22). Sodium amalgam (6%, 8 g) was

added in 2 g portions over a 30 min period to a stirred and

cooled (-12 °C) solution of compound 21 (1.00 g, 2.1 mmol) in

a 1:1 THF-MeOH mixture (40 mL) containing disodium

hydrogen phosphate (8.5 g, 60 mmol) (inert atmosphere). The

reaction mixture was stirred at -12 °C for 1 h and then

quenched with dilute aqueous HCl. After being partitioned

with ethyl acetate, the organic phase was worked up in the

usual manner, and crude product was purified by column

chromatography, using hexanes-ethyl acetate (1:1), followed

by dichloromethane-methanol (99:1) to elute 22 as an oil

(0.230 g, 49%): IR (neat) 3301, 1708 (w), 1682, 1545 cm^-1; MS

m/z (CI/NH₃) (rel intensity) 247 [(MNH₄)⁺, 100], 230 (MH⁺,

71), 191 (42); ¹³C NMR (330 K) δ 28.39 (3C), 32.22, 48.20, 66.65,

69.35, 80.25, 126.93, 129.57, 157.20. This compound was

directly converted into the crystalline acetonide 23.

28.38 (3C), 51.04, 69.11, 79.32 (2C), 82.2, 109.11, 130.02,

130.65, 155.43; HRMS calcd for C₁₄H₂₃NO₅286.1654, found

286.1631.

(()-Tetr a a cetyl Con d u r a m in e A-1 (27b). Trifluoroacetic

acid (0.5 mL) was added to a stirred solution of compound 26

(0.023 g, 0.08 mmol) in dichloromethane (0.5 mL). After 1 h,

water (0.5 mL) was added, and after an additional 1 h period,

the solvent was removed in vacuo. The residue was dissolved

in 2 M methanolic ammonia solution (10 mL), and after being

stirred for 2-3 h, the solvent was removed in vacuo to give a

residue which contained (()-conduramine A-1 (27a ). To this

material were added pyridine (1.5 mL), acetic anhydride (1.5

mL), and 4-(dimethylamino)pyridine (0.005 g), and after

stirring for 16 h, ethyl acetate was added to the reaction

mixture. The solution thus obtained was washed successively

with dilute HCl, saturated sodium carbonate solution, and

saturated NaCl solution and then dried. The solvent was

removed in vacuo, and pure (()-tetracetyl conduramine A-1

was isolated from the residue by column chromatography,

using hexanes-ethyl acetate (3:1) and dichloromethane-

methanol (99:1) as the eluants. Compound 27b was obtained

as a solid (0.023 g, 92% yield), which on crystallization from

hexanes-ethyl acetate, had mp 156-159 °C (reported^3amp

156-157 °C): ¹³C NMR δ 20.89, 20.95, 23.28, 47.78, 68.24,

69.59, 124.94, 131.32, 169.75, 170.01, 170.10, 170.88 (identical

to that published^8bfor (+)-conduramine A-1). Anal. Calcd for

Acet on id e

of

(()-3,4-cis-Dih yd r oxy-5-tr a n s-ter t-

bu toxyca r bon yla m in ocycloh exen e (23). This compound

was synthesized in the same manner as described for com-

pound 8 except that the reaction time was 4 h. The crude

product was purified by column chromatography, using hex-

anes-ethyl acetate (3:1) to elute pure 23 (85% yield): mp 110-

112 °C (hexanes-ethyl acetate); IR 3378, 3345, 1700 (sh), 1682

cm^-^{1 13}C NMR (315 K) δ 26.24, 28.15, 28.34 (3C), 28.94, 48.86,

;

71.86, 75.98, 79.80, 109.27, 125.04, 129.15, 155.59. Anal.

Calcd for C₁₁H₂₃NO₄: C, 62.43; H, 8.61; N, 5.20. Found: C,

62.49; H, 8.61; N, 5.09.

C

₁₄H₁₉NO₇: C, 53.67; H, 6.11; N, 4.47. Found: C, 53.40; H,

6.00; N, 4.23.

Aceton id e of (()-1,2-Ep oxy-a n ti-3,4-cis-d ih yd r oxy-5-

(()-1-p -Tolu en esu lfon yl-3,4-ep oxy-5-cis-ter t-b u t oxy-

ca r bon yla m in ocycloh exen e (28). A solution of the diene

15 (1.50 g, 4.3 mmol) in dichloromethane (25 mL) containing

m-chloroperoxybenzoic acid (1.3 g, 6.4 mmol) was stirred at

room temperature for 16 h. Saturated aqueous sodium

carbonate solution was added, and after thorough agitation,

the organic phase was worked up in the usual manner. The

crude product upon purification by column chromatography

(hexanes-ethyl acetate, 7:3) gave 28 as a solid (1.50 g, 91%

yield): mp 73-76 °C, after crystallization from hexanes-ethyl

tr a n s-ter t-bu tyoxyca r bon yla m in ocycloh exa n e (24).

A

mixture of 23 (0.035 g, 0.13 mmol), m-chloroperoxybenzoic acid

(0.053 g, 0.26 mmol), and sodium bicarbonate (0.022 g, 0.26

mmol) in dichloromethane (10 mL) was stirred at room

temperature for 16 h. The organic phase was separated and

then worked up in the usual manner. Purification of the crude

product by column chromatography, using hexanes-ethyl

acetate mixtures (95:5, 9:1 and 85:15), gave 24 as a solid (0.035

g, 95% yield) which, after crystallization from ethyl acetate-

hexane, had mp 66-68 °C (hexanes-ethyl acetate); IR (neat)

acetate; IR 3432, 1709, 1636, 1597, 1520, 1154 cm^-^{1 13}C NMR

;

3436, 1717 cm^-1

;

¹³C NMR δ 23.93, 25.79, 27.74, 28.40 (3C),

(320 K) δ 21.66, 26.31, 28.30, 46.24, 47.98, 57.25, 83.0, 128.27,

130.12, 131.63, 135.20, 143.61, 145.02, 155.0. Anal. Calcd for

42.59, 52.30, 52.45, 70.05, 73.11, 79.51, 109.76, 155.12. Anal.

Calcd for C₁₄H₂₃NO₅: C, 58.93; H, 8.13; N, 4.91. Found: C,

59.11; H, 7.99; N, 4.57.

C

₁₈H₂₃NO₅S: C, 59.16; H, 6.31; N, 3.83. Found: C, 59.18; H,

6.37; N, 3.77.

Aceton id e of (()-1-P h en ylselen o-tr a n s-2-h yd r oxy-a n ti-

3,4-cis-d ih yd r oxy-5-tr a n s-ter t-bu toxyca r bon yla m in ocy-

cloh exa n e (25). A solution of n-butyllithium in hexane (56

µL, 2.5 M, 0.14 mmol) was added to a stirred solution of

diphenyl diselenide (0.044 g, 0.14 mmol) in anhydrous THF

(5 mL, inert atmosphere). After 5 min, a solution of the

epoxide 24 (0.020 g, 0.07 mmol) in THF (2 mL) was added,

and stirring at room temperature was continued for 16 h.

Dilute hydrochloride acid was added to the reaction mixture,

followed by ethyl acetate. The organic phase was worked up

as usual. The crude product was purified by preparative TLC

on silica gel, using hexanes-ethyl acetate (1:1) as the develop-

ing solvent. Compound 25 was obtained as a solid (0.026 g,

84% yield): mp 55-58 °C (hexanes-ethyl acetate); IR 3428,

(()-1-p-Tolu en esu lfon yl-tr a n s-3,4-dih ydr oxy-syn -5-ter t-

bu toxyca r bon yla m in ocycloh exen e (29). A stirred solution

of compound 28 (0.45 g, 1.23 mmol) in THF (5 mL) containing

water (1 mL), and concentrated sulfuric acid (3 drops) was

heated at 80 °C for 3 h with periodic additions of small

amounts of THF to keep the reaction mixture homogeneous.

Ethyl acetate was added to the cooled reaction mixture, and

after the usual workup, pure 29 was isolated by column

chromatography, using dichloromethane-methanol (99:1) as

the eluting solvent. Compound 29 was obtained as a solid

(0.38 g, 81% yield): mp 172-173 °C (ethyl acetate-hexane);

IR 3411, 1682, 1597, 1516, 1291, 1150 cm^-^{1 13}C NMR (DMSO-

;

d₆, 330 K) δ 21.09, 24.90, 28.17 (3C), 46.24, 67.91, 70.43, 77.92,

127.75 (2C), 130.07 (2C), 135.13, 135.53, 139.53, 144.46,

154.90. Anal. Calcd for C₁₈H₂₅NO₆S: C, 56.38; H, 6.57; N,

3.65. Found: C, 56.27; H, 6.67; N, 3.47.

(()-tr a n s-3,4,-Dih yd r oxy-syn -5-ter t-b u t oxyca r b on yl-

a m in ocycloh exen e (30a ). This compound was prepared by

the method used for 22 except that 10 g of 6% sodium

amalgam/g of 29 was used, and the reaction temperature was

1686 cm^-^{1 13}C NMR δ 26.17, 27.95, 28.39 (3C), 32.73, 42.56,

;

48.49, 74.01, 77.20, 78.96, 109.59, 128.64, 129.25, 136.31,

148.9; HRMS calcd for C₂₀H₂₉NO₅⁷⁸Se 441.1219, found 441.1198.

Aceton id e of (()-N-ter t-Bu toxyca r bon yl Con d u r a m in e

A-1 (26). To a stirred and cooled (0 °C) solution of the

phenylseleno compound 25 (0.040 g, 0.090 mmol) in dichlo-

3248 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

-23 °C. After chromatographic purification, compound 30a

was obtained as a solid (76% yield) with mp 41-43 °C; IR 3418,

romethane-methanol (99:1) as the eluants; IR 3395, 1690,

1510 cm^-^{1 13}C NMR (330 K) δ 28.21, 28.44 (3C), 48.94, 67.96,

;

1686 cm^-1

;

¹³C NMR (325 K) δ 28.41 (3C), 48.02, 69.79, 73.56,

70.15, 79.74, 127.22, 127.44, 155.94; HRMS calcd for C₁₁H₁₉-

NO₄-C₃H₈173.0688, found 173.0688.

80.12, 126.94, 127.56, 156.75; HRMS calcd for [C₁₁H₁₉NO₄]H⁺

230.1392, found 230.1372.

(+)-cis-3(S),4(R)-Dih yd r oxy-syn -5(R)-ter t-bu toxyca r bo-

n yla m in ocycloh exen e [(+)-3(S),4(R),5(R)-35a ]. This com-

pound was prepared by the same method as used for (()-35a

except that a 12.5:1 g/g ratio of 6% sodium to (+)-18 was used.

Pure (+)-35a was obtained as an oil in 84% yield: MS m/z

(CI/NH₃) 247 [(MNH₄)⁺, 24], 230 [(MH)⁺, 100], 191 (85), 174

(26), 130 (94). Anal. Calcd for C₁₁H₁₉NO₄: C, 57.62; H, 8.35;

N, 6.11. Found: C, 57.03; H, 8.36; N, 6.02. [R]_D+34.0° (c 0.52,

CHCl₃).

(()-tr a n s-3,4,-Diacetoxy-syn -5-ter t-bu toxycar bon ylam i-

n ocycloh exen e (30b). This compound was prepared in

exactly the same manner as described for 27b. Compound 30b

was obtained pure by column chromatography, using hex-

anes-ethyl acetate (7:3) as the eluant. Pure 30b was obtained

as a solid (95% yield): mp 92-94 °C (hexanes-ethyl acetate);

IR (neat) 3366, 1740, 1713 cm^-^{1 13}C NMR (330 K) δ 21.04,

;

21.09, 28.35 (3C), 28.99, 45.73, 68.61, 72.08, 82.35, 123.07,

130.14, 155.2, 170.0, 170.4. Anal. Calcd for C₁₅H₂₃NO₆: C,

57.50; H, 7.40; N, 4.47. Found: C, 57.67; H, 7.36; N, 4.37.

(()-1,2-E p oxy-tr a n s-a n ti-3,4-d ia cet oxy-cis-5-ter t-b u -

toxyca r bon yla m in ocycloh exa n e (31). This compound was

prepared by the method described for the synthesis of 24

except that the reaction was carried out at 45 °C for 7 h.

Compound 31 was obtained pure (72% yield) by column

chromatography, using hexanes-ethyl acetate mixtures (4:1

and then 7:3) as the eluant. 31: mp 44-47 °C (hexanes-ethyl

(-)-cis-3(R),4(S)-Dih yd r oxy-syn -5(S)-ter t-bu toxyca r bo-

n yla m in ocycloh exen e [(-)-3(R),4(S),5(S)-35a ]. This com-

pound was prepared in the same manner as the dextrorotatory

enantiomer in 70% yield. Pure (-)-35a was an oil: MS m/z

(CI/NH₃) 247 [(MNH₄)⁺, 5], 230 [(MH)⁺, 100], 191 (39), 174

(53), 130 (29); [R]_D-33.7° (c 0.415, CHCl₃).

Aceton id e of (()-cis-3,4-Dih yd r oxy-syn -5-ter t-bu toxy-

ca r bon ylcycloh exen e (35b). This compound was prepared

from 35a by the method used to obtain compound 8 except

that the reaction time was 0.5 h. It was obtained pure (97%

yield) by column chromatography, using hexanes-ethyl ac-

etate (85:15) as the eluant, and had mp 72-74 °C after

crystallization from hexanes-ethyl acetate: IR 3383, 1717,

acetate); IR 1750, 1717 cm^-^{1 13}C NMR δ 20.95, 28.30 (3C),

;

43.66, 52.48, 54.09, 68.12, 72.04, 79.39, 155.6, 160.2, 160.8.

HRMS calcd for [C₁₅H₂₃NO₇C₄H₈]H⁺274.0927, found 274.0925.

(()-1-P h en ylselen yl-tr a n s-a n ti-tr a n s-2,3,4-tr ia cetoxy-

cis-5-ter t-bu toxyca r bon yla m in ocycloh exa n e (32b). Com-

pound 32a was first prepared by the method used to synthesize

25 except that a 5:1 molar ratio of lithium phenylselenide to

31 was used. Compound 32a was purified by column chro-

matography using hexanes-ethyl acetate (9:1) followed by

dichloromethane-methanol (99:1) as the eluting solvents. This

material was then converted into the triacetate 32b by the

method which had been used to convert compound 27a into

(()-tetraacetyl conduramine A-1 (27b). Crude 32b was ob-

tained pure by column chromatography, using hexanes-ethyl

acetate (85:15) as the eluant. Pure 32b was isolated as a solid

(60% yield): mp 163-166 °C (hexanes-ethyl acetate); IR 1751,

1518 cm^-^{1 13}C NMR δ 26.56, 26.63, 27.51, 28.36, 47.52, 73.34,

;

75.20, 79.50, 109.32, 126.15, 127.48, 155.31. Anal. Calcd for

₁₄H₂₃NO₄: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.32; H,

C

8.48; N, 5.12.

Aceton id e of (+)-cis-3(S),4(R)-Dih yd r oxy-syn -5(R)-ter t-

b u t oxyca r b on yla m in ocycloh exen e [(+)-3(S),4(R),5(R)-

35b]. This compound was prepared from (+)-3(S),4(R),5(R)-

35a by the same method which was used to prepare the

racemate. It was obtained in 94% yield and had mp 72-74

°C. Anal. Calcd for C₁₄H₂₃NO₄: C, 62.43; H, 8.61; N, 5.20.

Found: C, 62.83; H, 8.76; N, 5.18. [R]_D+61.5° (c, 0.522 CHCl₃).

Aceton id e of (()-1,2-Ep oxy-a n ti-cis-3,4-d ih yd r oxy-syn -

5-ter t-bu toxyca r bon yla m in ocycloh exa n e (36). This com-

pound was prepared by the method used to synthesize

compound 24. The crude product was obtained pure by column

chromatography, using hexanes-ethyl acetate mixtures (9:1

and then 4:1) to elute 36 as a thick clear oil (99% yield): IR

1716 cm^-^{1 13}C NMR (320 K) δ 20.67, 20.74 (2C), 28.28 (3C),

;

32.92, 37.52, 71.11, 71.61, 74.15, 80.2, 128.78, 129.27, 136.42,

155.30, 169.77, 169.85; MS m/z (rel intensity) 529 (MH⁺, 5),

351 (12), 316 (14), 292 (73), 290 (40), 274 (31), 256 (15), 249

(14), 196 (25), 154 (41), 110 (27), 57 (72), 43 (100). Anal. Calcd

for C₂₃H₃₁NO₈Se: C, 52.28; H, 5.91; N, 2.65. Found: C, 52.72;

H, 6.02; N, 2.65.

(neat) 3455, 3359, 1717, 1514 cm^-^{1 13}C NMR δ 25.11, 25.84,

;

27.59, 28.33 (3C), 41.94, 51.22, 53.10, 72.21, 74.27, 79.65,

109.81, 155.01; MS m/z (CI/NH₃) (rel intensity) 303 [(MNH₄)⁺,

11], 286 [(MH)⁺, 100], 247 (25), 230 (54), 171 (15), 127 (25).

Anal. Calcd for C₁₄H₂₃NO₅: C, 58.93; H, 8.13; N, 4.91.

Found: C, 58.83; H, 8.13; N, 4.11.

(()-Tr ia cetoxy-N-ter t-bu toxyca r bon yl Con d u r a m in e

F -1 (33). This compound was prepared in the same manner

as 26. Pure 33 was obtained as a solid (88% yield) after

column chromatography, using hexanes-ethyl acetate (3:1) as

the eluting solvent. Upon crystallization from hexanes-ethyl

acetate, it had the following properties: mp 110-112 °C; ¹³C

NMR δ 20.74, 20.82, 20.93, 28.26 (3C), 46.57, 68.69, 68.98,

71.58, 80.01, 127.56, 127.82, 155.15, 170.06, 170.20 (2C);

HRMS (FAB⁺) calcd for [C₁₇H₂₆NO₈]⁺372.1658, found 372.1678.

(()-Tetr a cetyl Con d u r a m in e F -1 (34b). A mixture of

compound 33 (0.025 g, 0.067 mmol), THF (0.5 mL), and 10%

HCl (1.5 mL) was heated at reflux temperature for 3 h. The

mixture was evaporated to dryness, and the residue was

sequentially reacted with methanolic ammonia and acetic

anhydride-pyridine-4-DMAP, as described for the prepara-

tion of (()-tetraacetyl conduramine A-1 (27b). Pure 34b was

obtained as a solid (0.020 g, 95% yield) by column chromatog-

raphy, using hexanes-ethyl acetate (7:3) and dichloromethane-

methanol (99:1) as the eluting solvents, and after crystalliza-

tion from hexanes-ethyl acetate, it had the following

properties: mp 139-141 °C (reported^3emp 142 °C); ¹³C NMR

δ 20.67, 20.76, 20.94, 23.26, 45.35, 68.54, 68.60 71.73, 127.44,

127.99, 169.89, 169.96, 170.18. Anal. Calcd for C₁₄H₁₉NO₇:

C, 53.67; H, 6.11; N, 4.47. Found: C, 53.41; H, 6.25; N, 4.30.

(()-cis-3,4-Dih yd r oxy-syn -5-ter t-b u t oxyca r b on yla m i-

n ocycloh exen e (35a ). This compound was prepared by the

method used for 22 except that the reaction was effected at

-22 °C, using 5 g of 6% sodium amalgam/g of 18. Pure 35a

was obtained as a clear glass (78% yield) by column chroma-

tography, using hexanes-ethyl acetate (4:1) and dichlo-

Aceton id e of (+)-1,2-Ep oxy-a n ti-cis-3,4-d ih yd r oxy-syn -

5-ter t-bu toxyca r bon yla m in ocycloh exa n e [(+)-36]. This

compound was prepared by the method used for (()-36 except

that the product was eluted from the column with hexanes-

ethyl acetate (4:1). The compound (+)-36 was obtained as a

glass in 97% yield. Anal. Calcd for C₁₄H₂₃NO₅: C, 58.93; H,

8.13; N, 4.91. Found: C, 59.13; H, 8.11; N, 4.53. [R]_D+57.2°

(c 0.495, CHCl₃).

Acet on id e of (()-1-P h en ylselen yl-tr a n s-2-h yd r oxy-

a n ti-cis-3,4-dih ydr oxy-syn -5-ter t-bu toxycar bon ylam in ocy-

cloh exa n e (37). This compound was prepared by the method

used to synthesize 25. Compound 37 was obtained pure by

column chromatography, using hexanes-ethyl acetate mix-

tures (9:1, 4:1, and 7:3 in succession) as the eluants. It was

isolated as a solid (86% yield) which, after crystallization from

hexanes-ethyl acetate, had the following properties: mp 140-

141 °C; IR 3470, 3252, 1703, 1501 cm^-^{1 13}C NMR δ 26.43;

;

28.14, 28.37 (3C), 33.38, 44.49, 48.46, 74.12, 75.79, 79.94 (2C),

109.79, 125.27, 128.71, 129.20 (2C), 136.58 (2C), 155.02; HRMS

calcd for C₂₀H₂₉NO₅⁷⁸Se 441.1219, found 441.1203.

Acet on id e of (-)-1-P h en ylselen yl-tr a n s-2-h yd r oxy-

a n ti-cis-3,4-dih ydr oxy-syn -5-ter t-bu toxycar bon ylam in ocy-

cloh exa n e [(-)-37]. This compound was prepared by the

method used to prepare the racemate except that the product

was eluted from the column with hexanes-ethyl acetate (7:

3). Pure (-)-37 was obtained in 85% yield and had mp 139-

Synthesis of Conduramines

J . Org. Chem., Vol. 63, No. 10, 1998 3249

140 °C. Anal. Calcd for C₂₀H₂₉NO₅Se: C, 54.30; H, 6.61; N,

3.17. Found: C, 54.59; H, 6.63; N, 3.08. [R]_D-69.9° (c 0.475,

CHCl₃).

(()-1,2-Ep oxy-cis-syn -3,4-d ih yd r oxy-cis-5-ter t-bu toxy-

ca r bon yla m in ocycloh exa n e (40). Prepared by the method

used for the synthesis of compound 24. Purification of the

crude product by column chromatography, using hexanes-

ethyl acetate (4:1), followed by dichloromethane-methanol (98:

2) as the eluants gave 40 as a solid (79% yield) which had mp

153-154 °C after crystallization from ethyl acetate-hexane:

Acet on id e of (()-3-H yd r oxy-a n ti-cis-4,5-d ih yd r oxy-

syn -6-ter t-bu toxyca r bon yla m in ocycloh exen e (38). This

compound was prepared by the method used for the synthesis

of 26. After purification by column chromatography with

hexanes-ethyl acetate mixtures (4:1 and then 1:1) as the

eluents, compound 38 was obtained as a solid (95% yield)

which, on crystallization from hexanes-ethyl acetate, had mp

104-106 °C; ¹³C NMR δ 24.50, 26.21, 28.40 (3C), 46.92, 65.22,

75.20, 77.88, 79.79, 108.59, 128.98, 134.62, 155.60; MS m/z (CI/

NH₃) (rel intensity) 303 [(MNH₄)⁺, 4], 288 (19), 286 (80), 247

(57), 232 (16), 230 (100), 186 (23), 171 (20), 127 (31). This

compound was not characterized further.

Acet on id e of (-)-3-H yd r oxy-a n ti-cis-4,5-d ih yd r oxy-

syn -6-ter t-bu toxycar bon ylam in ocycloh exen e [(-)-38]. This

compound was prepared by the method used for the racemate

in 97% yield. Pure (-)-38 had mp 95-99 °C. Anal. Calcd

for C₁₄H₂₃NO₅: C, 58.93; H, 8.12; N, 4.91. Found: C, 59.19;

H, 8.22; N, 5.04. [R]_D-56.0° (c 0.470, CHCl₃).

(()-Con d u r a m in e C-1 (39a ). A solution of compound 38

(0.407 g, 1.43 mmol) in trifluoroacetic acid (10 mL) and

dichloromethane (10 mL) was stirred at room temperature for

1 h, water (4 mL) was added, and stirring was continued for

another 1 h. The volatile materials were removed in vacuo,

the residue was dissolved in 2 M methanolic ammonia solution

(30 mL), and the solution was stirred at room temperature

for 16 h. The solvent was evaporated in vacuo, and the residue

was purified by column chromatography on Act II neutral

alumina using dichloromethane-methanol-concentrated am-

monium hydroxide (60:10:1) to elute (()-conduramine C-1 as

a white solid (0.134 g, 65% yield): mp 147-149 °C (hexanes-

ethyl acetate) (reported^8efor (+)- or (-)-conduramine C-1, mp

148-150 °C); ¹³C NMR (D₂O) δ 50.76, 68.86, 70.35, 73.78,

124.78, 131.06. This spectrum is similar, but not identical, to

a spectrum of (()-conduramine C-1 reported by Alleman and

Vogel^8fin MeOD. The differences probably are of solvent

origin since the properties of the tetraacetate 39b (see below)

are perfectly concordant with those reported.^8f

(-)-Con d u r a m in e C-1 [(-)-39a ]. A mixture of (-)-38

(0.083 g, 0.29 mmol) in THF (1 mL) and 5% hydrochloric acid

(5 mL) was heated at reflux temperature for 3 h. The solution

was evaporated to dryness in vacuo, and the residue was

dissolved in 2 M methanolic ammonia solution (10 mL). After

3 h, the solvent was removed in vacuo, and the residue was

purified in the manner described for the racemate. Pure (-)-

conduramine C-1 was obtained in 88% yield: mp 142-145 °C

(reported^8emp 148-150 °C); [R]_D-205° (c 0.490, MeOH)

(reported^8e[R]_D-221° (c 6.79, MeOH).

(()-Tetr a a cetyl Con d u r a m in e C-1 (39b). This com-

pound was prepared directly from 38 by the method that was

used to obtain (()-tetraacetyl conduramine A-1 (27b) from 26.

It was obtained as a solid (97% yield) by preparative TLC on

silica gel, using hexanes-ethyl acetate as the developing

solvent. After crystallization from ethyl acetate-hexane, it

had mp 142-143 °C (reported^8fmp 143-145 °C for (-)-

tetraacetyl conduramine C-1). The ¹³C NMR spectrum was

completely identical to that reported^8ffor this compound.

Anal. Calcd for C₁₄H₁₉NO₇: C, 53.67; H, 6.11; N, 4.47.

Found: C, 53.39; H, 5.93; N, 4.22.

(-)-Tetr a a cetyl Con d u r a m in e C-1 [(-)-39b]. A solution

of (-)-38 (0.053 g, 0.19 mmol) in THF (1 mL) was mixed with

5% hydrochloric acid (5 mL), and the mixture was heated at

reflux temperature for 3 h. The solution was evaporated to

dryness in vacuo, and pyridine (2 mL) and acetic anhydride

(2 mL) were added to the residue. The mixture was stirred

for 16 h and evaporated to dryness, toluene was added, and

the mixture was evaporated in vacuo (a total of three times).

Pure (-)-39b was obtained from the residue by column

chromatography, using ethyl acetate as the eluant. It was

obtained in 95% yield as a solid mp 140-142 °C (reported^8f

mp 143-145 °C); [R]_D-178° (c 0.995, CH₂Cl) [reported^8f[R]_D

-181° (c 1.0, CH₂Cl₂). The ¹³C NMR spectrum was identical

to that reported for this compound by Allemann and Vogel.^8f

IR 3420, 3347, 1694, 1532 cm^-^{1 13}C NMR (DMSO-d₆, 315 K)

;

δ 24.90, 28.12, 48.65, 51.53, 55.23, 66.73, 70.49, 79.07, 154.60.

Anal. Calcd for C₁₁H₁₉NO₅: C, 53.87; H, 7.81; N, 5.71.

Found: C, 54.05; H, 7.80; N, 5.67.

(-)-1,2-Ep oxy-cis-syn -3,4-d ih yd r oxy-cis-5-ter t-bu toxy-

ca r bon yla m in ocycloh exa n e [(-)-40]. This compound was

prepared by the method used for 24 except that pure (-)-40

was eluted from the column as an oil in 75% yield, using

dichloromethane-methanol mixtures (99:1 then 96:4) as the

eluting solvents. Anal. Calcd for C₁₁H₁₉NO₅: C, 53.87; H,

7.81; N, 5.71. Found: C, 53.49; H, 7.77; N, 5.73. [R]_D-26.2°

(c 0.625, CHCl₃).

(()-1-P h en ylselen yl-a n ti-cis-syn -2,3,4-t r ih yd r oxy-cis-

5-ter t-bu toxyca r bon yla m in ocycloh exa n e (41a ). This com-

pound was prepared by the method used to synthesize 25

except that the ratio of lithium phenylselenide to 40 was 4:1,

and the reaction time was 1.5 h. Pure 41a was obtained as a

solid (72% yield) by column chromatography, using hexanes-

ethyl acetate (4:1 then 98:2), followed by dichloromethane-

methanol (96:4) as the eluting solvents. Compound 41a : mp

55-59 °C; IR 3414, 1713 (sh), 1682, 1578 cm^-^{1 1}H NMR δ

;

1.44 (s, 9H), 1.57-1.65 (m, 1H), 2.27 (ddd, 1H, J ) 4.0, 6.8,

14.3 Hz), 3.46 (m, 1H), 3.57 (bm, 1H), 3.68 (bt, 1H), 3.98 (bm,

1H), 4.14 (t, 1H), 5.54 (bd, 1H), 7.26-7.36 (m, 3H), 7.57 (m,

2H). MS m/z (rel intensity) 403 (M⁺, 9), 385 (13), 293 (39),

291 (18), 173 (14), 154 (12), 111 (14), 110 (17), 57 (100). Anal.

Calcd for C₁₇H₂₅NO₅Se: C, 50.75; H, 6.26; N, 3.48. Found:

C, 50.28; H, 6.31; N, 3.70.

(()-1-P h en ylselen yl-a n ti-cis-syn -2,3,4-tr ia cetoxy-cis-5-

ter t-bu toxyca r bon yla m in ocycloh exa n e (41b). Chromato-

graphically pure 41a , prepared as described above, was

peracetylated by the method that was used to prepare (()-

tetraacetyl conduramine A-1 (27b). The crude tetraacetyl

compound 41b was purified by column chromatography, using

hexanes-ethyl acetate mixtures (85:15 and then 7:3) as the

eluting solvents. Compound 41b was obtained as a solid (70%

yield from 40): mp 65-68 °C (hexanes-ethyl acetate); IR 3451,

1752, 1722, 1634 cm^-^{1 13}C NMR δ 20.64 (2C), 20.80, 28.38

;

(3C), 33.71, 35.16, 48.07, 68.32, 70.98, 71.78, 79.66, 128.72,

129.25, 155.37, 169.09, 169.37, 169.53. Anal. Calcd for

C

₂₃H₃₁NO₈Se: C, 52.27; H, 5.91; N, 2.65. Found: C, 51.96;

H, 5.95; N, 2.54.

(+)-1-P h en ylselen yl-a n ti-cis-syn -2,3,4-tr ia cetoxy-cis-5-

ter t-bu toxyca r bon yla m in ocycloh exa n e [(+)-41b]. The

epoxy compound (-)-40 was first converted into the phenylse-

lenyl compound (+)-41a by the method used to prepare (()-

37, and (+)-41a was then peracetylated by the method used

to prepare (()-tetraacetyl conduramine A-1 (27b). Pure (+)-

41b was eluted from the column using hexanes-ethyl acetate

mixtures (9:1 and then 7:3). The purified solid (69% yield)

had mp 130-132 °C. Anal. Calcd for C₂₃H₃₁NO₈Se: C, 52.27;

H, 5.91; N, 2.65. Found: C, 52.51; H, 6.00; N, 2.53. [R]_D

+84.5° (c 0.620, CHCl₃).

(()-Tr ia cetoxy-N-ter t-bu toxyca r bon yl Con d u r a m in e

D-1 (42). Compound 42 was prepared by the technique used

to prepare 26. It was obtained pure as a solid (90% yield) by

column chromatography, using hexanes-ethyl acetate mix-

tures (9:1 then 7:3) as the eluting solvents. 42: mp 45-49 °C

(hexanes-ethyl acetate); IR (neat) 3461, 3376, 1707 cm^-^{1 13}C

;

NMR δ 20.73 (2C), 20.67, 28.36 (3C), 46.09, 67.08, 67.28, 68.84,

79.73, 126.06, 129.02, 155.3, 169.65, 169.9. Anal. Calcd for

C

₁₇H₂₅NO₈: C, 54.98; H, 6.78; N, 3.77. Found: C, 54.65; H,

6.68; N, 3.60.

(+)-Tr ia cetoxy-N-ter t-bu toxyca r bon yl Con d u r a m in e

D-1 [(+)-42]. This compound was prepared in 91% yield by

the method used to prepare the racemate. (+)-42): mp 47-

50 °C; HRMS calcd for C₁₇H₂₅NO₈371.1580, found 371.1558;

[R]_D+124° (c 0.525, CHCl₃).

3250 J . Org. Chem., Vol. 63, No. 10, 1998

Leung-Toung et al.

(()-Con d u r a m in e D-1 Hyd r och lor id e (43a ). A mixture

of 42 (0.090 g, 0.24 mmol) and 5 N hydrochloric acid (5 mL)

was heated at reflux temperature for 3 h. The cooled solution

was washed with ethyl acetate, and the aqueous phase was

evaporated in vacuo to give 43a as a glass (0.042 g, 95%

yield): ¹³C NMR (CD₃OD) δ 49.86, 66.77, 68.89, 72.93, 122.37,

136.51; HRMS (FAB⁺) calcd for [C₆H₁₁NO₃H]⁺146.0817, found

146.0821.

(+)-Con d u r a m in e D-1 Hyd r och lor id e [(+)-43a ]. This

compound was prepared by the method used to prepare the

racemate and obtained in 82% yield as a very hygroscopic

solid: mp 156-161 °C; MS m/z (FAB⁺, relative intensity) 146

(MH⁺, 100); [R]_D+120.3° (c 0.600, MeOH).

65.05, 70.91, 75.06, 82.57, 128.01, 130.02, 132.88, 135.80,

136.61, 145.40, 154.97, 172.97. Anal. Calcd for C₂₁H₂₇NO₇S:

C, 57.65; H, 6.22; N, 3.20. Found: C, 57.25; H, 6.18; N, 3.13.

[R]_D+12.5° (c 0.998, CHCl₃).

In the same manner as (+)-44b, compound (-)-45b was

obtained as a solid (94% yield): mp 110-112 °C after crystal-

lization from ethyl acetate-hexane; IR 3391, 3227, 1737, 1709,

1597, 1370, 1152 cm^-^{1 13}C NMR δ 18.35, 21.54, 28.19, 60.24,

;

65.69, 70.26, 74.07, 81.31, 128.14, 129.94, 133.24, 136.18,

136.72, 145.21, 154.08, 174.75. Anal. Calcd for C₂₁H₂₇NO₇S:

C, 57.65; H, 6.22; N, 3.20. Found: C, 57.23; H, 6.22; N, 3.31.

[R]_D-36.35° (c 0.985, CHCl₃).

C. Syn th esis of th e Dia ster eom er ic Hyd r oxym eth yl

Com p ou n d s (+)-46 a n d (-)-47 fr om th e Ester s (-)-44a

a n d (-)-45a , Resp ectively. A mixture of powdered sodium

borohydride (12.8 g, 340 mmol) and tetrahydrofuran (500 mL)

containing (-)-44a (19.0 g, 42.1 mmol) and methanol (34 mL)

was stirred at 70 °C for 2 h. The cooled solution was made

acidic with dilute hydrochloric acid, the volatile materials were

removed in vacuo, and the residue was partitioned between

water and ethyl acetate. The organic phase was worked up

as usual and the crude product was purified by column

chromatography using hexanes-ethyl acetate mixtures (9:1

and then 3:2) to elute solid (+)-46 (16.9 g, 95% yield) which,

on crystallization from ethyl acetate-hexane, had the follow-

ing properties: mp 105-107 °C; IR 3428, 1682, 1593, 1381,

(()-Tetr a cetyl Con d u r a m in e D-1 (43b). A solution of 42

(0.200 g, 0.54 mmol) in THF (2 mL) and 5 N HCl (7 mL) was

heated at reflux temperature for 3 h. The solution was

evaporated in vacuo, acetic anhydride (5 mL) and pyridine (5

mL) were added to the residue, and the mixture was stirred

for 16 h. The solvent was removed in vacuo, toluene was

added, and the mixture was evaporated in vacuo. The addition

and removal of toluene was carried out a total of three times,

and the residue was taken up in ethyl acetate and filtered

through silica gel. A solid (0.161 g, 95% yield) was obtained

which, on crystallization from ethyl acetate-hexane, had the

following properties: mp 147-149 °C; IR 3395, 3272, 1748,

1651, 1545 cm^-1

67.05, 126.26, 128.73, 169.27, 169.57. Anal. Calcd for

₁₄H₁₉NO₇: C, 53.67; H, 6.11; N, 4.47. Found: C, 53.36; H,

;

¹³C NMR δ 20.70, 20.91, 23.32, 44.66, 66.62,

1370, 1163, 1146 cm^-^{1 13}C NMR δ 15.31, 21.49, 28.02 (3C),

;

C

59.77, 64.86, 66.52, 70.33, 78.01, 81.54 (2C), 127.9 (2C), 129.92

(2C), 132.67, 134.99, 136.80, 144.91, 153.94. Anal. Calcd for

6.26; N, 4.25.

Gen er a tion of (-)-3c-a n d (+)-3c fr om (()-2-p-Tolu en e-

s u lfo n y l-7-t er t -b u t o x y c a r b o n y l-7-a za b ic y c lo [2.2.1]-

h ep ta d ien e (3c). A. F or m a tion of Dia ster iom er ic Ad -

d u cts 44a a n d 45a w ith (-)-Meth yl La cta te. A solution

of (-)-methyl lactate (10.4 g, 100 mmol) in dry THF (15 mL)

was added to a stirred suspension of sodium hydride (0.300 g,

60% dispersion in mineral oil, 7.5 mmol) in dry THF (300 mL).

After ca. 10 min, a solution of (()-3c (34.7 g, 100 mmol) in

dry THF (100 mL) was added, and the reaction mixture was

stirred for 2 h. Ethyl acetate and a dilute aqueous ammonium

chloride solution were added, and the organic phase was

separated and worked up as usual. Removal of the solvent in

vacuo gave a residue which was subjected to column chro-

matographic purification, using hexanes-ethyl acetate (4:1)

to elute a mixture of 44a and 45a (43.3 g, 96% yield). This

material was dissolved in the minimum amount of hot 4:1

hexanes-ethyl acetate, and the solution was left to cool (finally

in the refrigerator).

C

₂₁H₂₉NO₆S: C, 59.55; H, 6.90; N, 3.31. Found: C, 59.61; H,

6.97; N, 3.23. [R]_D+63.5° (c 0.104, CHCl₃).

The diastereomeric alcohol (-)-47 was prepared exactly as

described for (+)-46 and was obtained as a solid (94% yield)

which, after crystallization from ethyl acetate-hexane, had

the following properties: mp 99-100 °C; IR 3513, 3440, 1707,

1618, 1599, 1367, 1165, 1150 cm^-^{1 13}C NMR δ 16.99, 21.51,

;

27.85, 59.37, 66.20, 66.91, 69.62, 77.0, 80.88, 81.12, 127.84

(2C), 130.09 (2C), 133.06, 135.47, 136.07, 145.17, 154.27. Anal.

Calcd for C₂₁H₂₉NO₆S: C, 59.55; H, 6.90; N, 3.31. Found: C,

59.47; H, 6.92; N, 3.51. [R]_D-38.3° (c 0.107, CHCl₃).

(-)-2-p -T o lu e n e s u lfo n y l-7-t er t -b u t o x y c a r b o n y l-7-

a za bicyclo[2.2.1]h ep ta d ien e [(-)-3c] fr om (+)-44b or (+)-

46. The method used was identical for both precursors of (-)-

3c, and a typical procedure using (+)-44b follows. All solvents

were degassed prior to use by bubbling a slow stream of argon

through the ultrasonically irradiated solvent for 5-10 min. A

solution of methylmagnesium bromide in 3:1 toluene-THF

(1.57 mL of a 1.4 M solution, 2.2 mmol) was added dropwise

over ca. 5 min to a stirred solution of (+)-44b (0.437 g, 1 mmol)

in dry THF (10 mL, argon atmosphere) at room temperature.

Stirring was continued for an additional 5 min, and then the

reaction was quenched by the addition of excess dilute

hydrochloric acid. The mixture was extracted with ethyl

acetate, the extract was washed successively with dilute

aqueous NaOH and saturated aqueous NaCl solution, and then

it was dried and evaporated in vacuo. Pure (-)-3c was

obtained as a solid (0.323 g, 93% yield) by column chromatog-

raphy using hexanes-ethyl acetate (85:15) as the eluting

solvent. It had mp 105-106 °C, was pure by HPLC (see

synthesis of (()-3c), and had the longer retention time (∼25

min). Anal. Calcd for C₁₈H₂₁NO₄S: C, 62.23; H, 6.09; N, 4.03.

Found: C, 62.43; H, 6.14; N, 3.96. [R]_D-93.5° (c 1.0015,

CHCl₃).

Diastereomer 45a (21.3 g, 47%) was collected by filtration.

The filtrate was concentrated in vacuo, and the residue on

crystallization from hexanes-ethyl acetate gave diastereomer

44a (21.6 g, 48% yield).

Diastereomer 44a : mp 81-82 °C; IR 3440, 1752, 1707, 1638,

1597, 1370, 1152 cm^-^{1 13}C NMR δ 18.63, 21.51, 27.99 (3C),

;

51.92, 59.98, 67.72, 70.18, 74.72, 80.86, 81.60, 127.88 (2C),

130.06 (2C), 133.2, 135.61, 136.20, 145.08, 154.9, 172.2. Anal.

Calcd for C₂₂H₂₉NO₇S: C, 58.52; H, 6.47; N, 3.10. Found: C,

58.71; H, 6.55; N, 3.03. [R]_D- 25.1° (c 0.1035, CHCl₃).

Diastereomer 45a : mp 126-127 °C; IR 3440, 1752, 1690,

1368, 1156 cm^-^{1 13}C NMR δ 18.61, 21.51, 28.00, 51.87, 59.79,

;

64.59, 66.30, 73.75, 80.80, 81.85, 127.81 (2C), 129.87 (2C),

132.58, 135.8, 136.20, 144.72, 154.06, 172.64. Anal. Calcd for

C

₂₂H₂₉NO₇S: C, 58.52; H, 6.47; N, 3.10. Found: C, 58.76; H,

6.52; N, 3.05. [R]_D-50.4° (c 0.113, CHCl₃).

B. Sa p on ifica tion of th e Dia ster eom er ic Ester s (-)-

44a a n d (-)-45a to th e Ca r boxylic Acid s (+)-44b a n d (-)-

45b, Resp ectively. A solution of ester (-)-44a (4.51 g, 10

mmol) in tetrahydrofuran (20 mL) was added to a solution of

sodium hydroxide (1.20 g, 30 mmol) in methanol (50 mL), and

the reaction mixture was stirred at room temperature for 16

h. The volatile material was removed in vacuo, and the

residue was partitioned between ethyl acetate and water. The

aqueous phase was made acidic with concentrated hydrochloric

acid, and the liberated carboxylic acid (+)-44b was extracted

into the ethyl acetate. After the usual workup the crude acid

was crystallized from ethyl acetate-hexane to give pure (+)-

44b (4.05 g, 93% yield): mp 112-115 °C; IR 3428, 1744, 1709,

When (+)-46 was used as the starting material, (-)-3c was

obtained in 95% yield.

(+)-2-p -T o lu e n e s u lfo n y l-7-t er t -b u t o x y c a r b o n y l-7-

a za bicyclo[2.2.1]h ep ta d ien e [(+)-3c] fr om (-)-45b or (-)-

47. Using the methodology described above (+)-3c was

obtained in 92% and 95% yields from (-)-45b and (-)-47,

respectively. The compound (+)-3c had mp 107-108 °C, was

pure by HPLC, and had a retention time of ca. 22 min. Anal.

Calcd for C₁₈H₂₁NO₄S: C, 62.23; H, 6.09; N, 4.03. Found: C,

62.49; H, 6.12; N, 4.02. [R]_D+95.6° (c 0.967, CHCl₃).

1597, 1370, 1154 cm^-1

;

¹³C NMR δ 17.75, 21.59, 28.17, 60.32,

J O971907R

Article Doi

Synthesis of conduramines from N-tert-butoxycarbonylpyrrole

DOI: 10.1021/jo971907r

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Article abstract of DOI:10.1021/jo971907r

Full text of DOI:10.1021/jo971907r

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