Tandem inter [4 + 2]/intra [3 + 2] cycloadditions of nitroalkenes. Asymmetric synthesis of highly functionalized aminocyclopentanes using the bridged mode (β-tether) process

6178

J . Org. Chem. 1998, 63, 6178-6195

Ta n d em In ter [4 + 2]/In tr a [3 + 2] Cycloa d d ition s of Nitr oa lk en es.

Asym m etr ic Syn th esis of High ly F u n ction a lized

Am in ocyclop en ta n es Usin g th e Br id ged Mod e (â-Teth er ) P r ocess^†

Scott E. Denmark* and J ulie A. Dixon

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801

Received February 6, 1998

An asymmetric, tandem inter [4 + 2]/intra [3 + 2] bridged mode (â-tether) cycloaddition of

nitroalkenes has been developed. This new sequence involves the Lewis acid-promoted [4 + 2]

cycloaddition of nitro olefins with enantiopure 1-alkoxy-1,4-dienes. The resulting nitronates, bearing

a C(5) tethered dipolarophile, undergo thermal, intramolecular [3 + 2] cycloaddition to afford stable

tricyclic nitroso acetals, which can be subsequently reduced to provide interesting aminocyclopen-

tanes. Thus, in three steps, highly functionalized, enantiomerically enriched aminocyclopentanes

can be constructed with good yield and high ee. Additionally, the Lewis acid was found to impart

a remarkable influence on the stereochemical outcome of the [4 + 2] cycloaddition.

In tr od u ction

Asymmetric variants of the hetero-Diels-Alder reac-

tion can be used to assemble a variety of chiral, nonra-

cemic heterocyclic frameworks with good enantioselec-

tivity.¹As part of our research program involving inverse

electron-demand nitroalkene cycloadditions, we have

developed asymmetric, tandem [4 + 2]/[3 + 2] cycload-

ditions using nitro olefins and chiral vinyl ethers.²This

process allows for the rapid and predictable construction

of highly functionalized nitrogen-containing compounds

with high diastereo- and enantioselectivity.

The preceding report in this issue detailed the de-

velopment of the bridged-mode (â-tether) tandem inter

[4 + 2]/intra [3 + 2] cycloaddition of (E)-2-methyl-2-

nitrostyrene with 1-butoxy-1,4-pentadiene, Scheme 1.³

Sch em e 1

F igu r e 1. Selected aminocyclopentanol-derived natural prod-

ucts and carbocyclic nucleosides.

and carbocyclic nucleosides, Figure 1. Aminocyclopen-

titol-derived natural products such as mannostatin A,⁴

allosamizoline,⁵and trehazolin⁶have been reported to be

potent glycosidase inhibitors.⁷Since glycosidase-process-

ing enzymes perform critical roles in intra- and intercel-

The tandem cycloadducts were reduced to afford, after

protection, highly functionalized aminocyclopentanedi-

methanol triacetates.

Aminocyclopentanols comprise an important structural

motif which is common to a variety of biologically

interesting compounds including glycosidase inhibitors

(2) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.

(b) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J . Org. Chem.

1993, 58, 1859. (c) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.;

Thorarensen, A. J . Org. Chem. 1995, 60, 3205. (d) Denmark, S. E.;

Thorarensen, A. J . Am. Chem. Soc. 1997, 119, 127. (e) Denmark, S.

E.; Hurd, A. R.; Sacha, H. J . J . Org. Chem. 1997, 62, 1668. (f) Denmark,

S. E.; Marcin, L. R. J . Org. Chem. 1997, 62, 1675. (g) Denmark, S. E.;

Guagnano, V.; Dixon, J . A.; Stolle, A. J . Org. Chem. 1997, 62, 4610.

(3) Denmark, S. E.; Dixon, J . A. J . Org. Chem. 1998, 63, 6167.

(4) (a) Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Morisha, H.; Nagai, M.;

Hamada, M.; Takeuchi, T.; Umezawa, H. J . Antibiot. 1989, 42, 883.

(b) Morishima, H.; Kojiri, K, Yamamoto, T.; Aoyagi, T.; Nakamura,

H.; Iitaka, Y. J . Antibiot. 1989, 42, 1008.

^†Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. 20.

(1) (a) Tietze, L. F.; Kettschau, G. In Topics in Current Chemistry,

Vol. 189; Metz, P., Ed.; Springer: New York, 1997; pp 1-120. (b)

Waldmann, H. Synthesis 1994, 535. (c) Kagan, H. B.; Riant, O. Chem.

Rev. 1992, 92, 1007.

Published on Web 08/21/1998

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6179

Sch em e 2

lular transport and signal transduction, inhibition of

these enzymes has therapeutic ramifications on im-

munology, virology, and oncology.⁸Additionally, car-

bocyclic nucleosides have received considerable attention

due to their remarkable antiviral and antitumor activi-

ties.⁹More specifically, carbovir¹⁰and aristeromycin¹¹

have shown potent and selective anti-HIV activity. Cur-

rent interest in aminocyclopentanols stems not only from

their interesting biological activity but also from a

synthetic point of view. The high degree of functionality

poses a significant challenge and creates opportunity for

the development of new methods to construct these

frameworks in enantiomerically enriched form.

This paper provides a detailed account of our studies

on the asymmetric, bridged-mode (â-tether) tandem se-

quence ([4 + 2]/[3 + 2]/cleavage) employing nitroalkenes

and enantiomerically enriched 1-alkoxy-1,4-pentadienes.

Additionally, a novel influence of the Lewis acid on the

stereochemical outcome of the [4 + 2] cycloaddition will

be addressed. A preliminary report on the asymmetric

bridged-mode (â-tether) process has appeared.¹²

nitroalkene complex.^2bInterestingly, a number of Lewis

acid dependent reversals in selectivity have been docu-

mented for a variety of reactions including asymmetric

Diels-Alder,¹³aldol,¹⁴and 1,4-addition reactions.¹⁵In

some examples, the switch in selectivity is rationalized

by invoking different coordination modes of the Lewis

acids, while in other systems the reversal is believed to

result from differing steric requirements of the Lewis

acids.

Syn th esis of Am in ocyclop en ta n ols. The first and

most common approach for the asymmetric construction

of aminocyclitols involves the fragmentation and func-

tional group manipulation of natural carbohydrates.

Several syntheses of trehazolin aglycon, allosamizoline,

mannostatin A, and various aminocyclopentitol deriva-

tives utilize carbohydrate precursors such as ^D-glucose,

D-ribose, D-glucosamine, and D-ribonolactone.¹⁶Addition-

ally, a variety of carbocyclic nucleosides have been

prepared from ^D-ribose, D-glucono-δ-lactone, and other

chiral precursors such as amino acids.¹⁷

Another common strategy for the preparation of ami-

nocyclopentane moieties is the use of heteroatomic cy-

cloaddition reactions. The key step in a number of

aminocyclopentanol syntheses involves asymmetric het-

ero-Diels-Alder reactions of substituted cyclopentadienes

and enantiopure acylnitroso species, Scheme 3.¹⁸Hy-

drogenolytic cleavage of the resulting cycloadducts fol-

lowed by dihydroxylation provides the desired aminocy-

clopentitols or nucleosides. Additionally, intramolecular

Ba ck gr ou n d

Asym m etr ic Ta n d em Cycloa d d ition s. Enantio-

merically enriched, chiral vinyl ethers have served

admirably as the 2π components in asymmetric tandem

cycloadditions.²For example, tandem [4 + 2]/[3 + 2]

cycloadditions of nitroalkene 1 with enantiopure vinyl

ether (-)-2, derived from (-)-2,2-diphenylcyclopentanol,

afford intermediate nitroso acetals with exceptional

diastereoselectivity when promoted by Ti(O-i-Pr)₂Cl₂or

methylaluminum bis(2,6-diphenylphenoxide) (MAPh),

Scheme 2.^2cAfter hydrogenolytic unmasking of the

nitroso acetals, the R-hydroxy lactam 3 is produced with

high enantiomeric purity (98-93% ee), whose absolute

configuration is dependent upon the Lewis acid promoter

employed in the initial [4 + 2] cycloaddition. This

remarkable Lewis acid dependence on the stereochemical

outcome of the [4 + 2] cycloaddition has been attributed

to a switch in the approach (endo/exo) of one face of the

vinyl ether to the enantiotopic faces of the Lewis acid-

(13) (a) Tietze, L. F.; Schneider, C.; Grote, A. Chem. Eur. J . 1996,

58, 139. (b) Tietze, L. F.; Schneider, C. Synlett 1992, 755. (c) Tietze, L.

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1988, 53, 6133. (d) Suzuki, H.; Mochizuki, K.; Hattori, T.; Takahashi,

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Poll, T.; Helmchen, G.; Bauer, B. Tetrahedron Lett. 1984, 25, 2191.

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1987, 40, 296. (b) Nishimoto, Y.; Sakuda, S.; Takayama, S.; Yamada,

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V. J .; Gooday, G. W.; Stark, M. J . R. Eur. J . Biochem. 1991, 199, 483.

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7, 50.

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1116.

(7) Review: (a) Yoshikuni, Y. Trends Glycosci. Glycotechnol. 1991,

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184.

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1994, 59, 4450. (f) Li, C.; Fuchs, P. L. Tetrahedron Lett. 1994, 35, 5121.

(g) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J . Org. Chem. 1994, 59,

813. (h) Knapp, S.; Purandare, A.; Rupitz, K.; Withers, S. G. J . Am.

Chem. Soc. 1994, 116, 7461. (i) Marco-Contelles, J .; Destabel, C.;

Chiara, J . L.; Bernabe´, M. Tetrahedron: Asymmetry 1995, 6, 1547. (j)

Chiara, J . L.; Marco-Contelles, J .; Khiar, N.; Gallego, P.; Destabel, C.;

Bernabe´, M. J . Org. Chem. 1995, 60, 6010. (k) Kiguchi, T.; Tajiri, K.;

Ninomiya, I.; Naito, T. Tetrahedron Lett. 1995, 36, 253. (l) For a recent

review on the use of carbohydrate templates for the preparation of

carbocycles, see: Ferrier, R. J .; Middleton, S. Chem. Rev. 1993, 93,

2779.

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(9) For general reviews on the synthesis of carbocyclic nuleosides

see: (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.

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1 1994, 613. (c) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K.

Tetrahedron Lett. 1997, 38, 4207. (d) Katagiri, N.; Matsuhashi, Y.;

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(12) Denmark, S. E.; Dixon, J . A. J . Org. Chem. 1997, 62, 7086.

6180 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

Sch em e 3

pentane ring systems are created using carbohydrate

precursors. While these are often inexpensive staring

materials, they frequently require the use of many

additional steps for the installation, removal, and inter-

conversion of various functional groups. Thus, a more

concise and general method for the asymmetric synthesis

of aminocyclopentanols would still have merit.

nitrile oxide, nitrone, and oxime cycloadditions have been

used in the preparation of aminocyclopentanols.¹⁹

A third approach for the asymmetric synthesis of

aminocyclopentitols and carbocyclic nucleosides involves

the desymmetrization of functionalized cyclopentenyl-1,4-

meso-diols, using enzyme-mediated hydrolyses²⁰or pal-

ladium-catalyzed asymmetric allylic alkylations,²¹Scheme

4. Subsequent functionalization of the double bond

affords highly oxygenated aminocyclopentanes.

Resu lts

Syn th esis of 1-Alk oxy-1,4-p en ta d ien es. Prepara-

tion of chiral, nonracemic dienophiles for use in the

â-bridged-mode tandem process was accomplished in two

steps from (-)-(1R,2S)-phenylcyclohexanol ((-)-4). Fol-

lowing the method of Greene,²³the potassium salt of (-)-4

(>99% ee) was combined sequentially with trichloro-

ethylene and n-butyllithium, to afford, after quenching

with allyl iodide, the acetylenic ether (-)-5 in 83% yield,

Scheme 6. Lithium aluminum hydride reduction of (-)-5

provided exclusively the trans vinyl ether (-)-6 in 85%

yield.²⁴Alternatively, the cis vinyl ether (-)-7 was

stereoselectively obtained from a diisobutylaluminum

hydride (DIBAL) reduction of (-)-5. Additionally, trans

vinyl ethers, derived from 2,2-diphenylcyclopentanol and

2-(1-methyl-1-phenylethyl)cyclohexanol (TCC), were pre-

pared in a similar fashion.

Sch em e 4

The last method reported for the asymmetric construc-

tion of aminocyclopentitols uses a cyclopropylcyclopen-

tadiene as the key intermediate, Scheme 5. This inter-

Sch em e 5

Sch em e 6

Cycloa d d ition s a n d Red u ction s of Nitr o Olefin 8

w ith Tr a n s Vin yl Eth er (-)-6. The [4 + 2] cycloaddi-

tion of nitroalkene 8²⁵with (-)-6 was efficiently promoted

by SnCl₄to afford a mixture of diastereomeric nitronates

9a , 9b, and 9d (32/2/1) in 93% yield, Table 1. Diaster-

eomers 9a and 9b possess a cis relationship between the

C(4)-phenyl and C(5)-allyl substituents and are believed

to retain the trans relationship of the vinyl ether. Thus,

they must arise from an endo-(allyl), exo-(alkoxy) mode

cycloaddition. The trans (C(4)/C(5)) nitronate 9d , whose

stereostructure was secured through X-ray analysis²⁶

may result from an endo-(alkoxy), exo-(allyl) mode reac-

tion, which provides nitronate 9c, followed by epimer-

ization of the C(6) acetal center. Alternatively, an

isomerization of the trans vinyl ether to a cis vinyl ether

followed by an exo-(alkoxy) mode cycloaddition may be

operative.²⁷The nitronic ester subunits of 9a and 9b are

enantiomorphic and arise from exo-mode cycloadditions

from combinations of unlike (ul)²⁸diastereotopic faces of

esting species is generated from the reaction of epichloro-

hydrin with lithium cyclopentadienide.²²Amidohydrox-

ylation and functionalization provided the aglycon of

trehazolin.

While there are various methods for the asymmetric

preparation of aminocyclopentanoid products, several

limitations still remain. For example, many of the routes

employ a preexisting cyclopentane ring that limits the

range of functionality and substitution which can be

efficiently incorporated. In addition, some of the cyclo-

(18) (a) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1991, 113, 5089.

(b) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1994, 116, 562. (c)

Goering, B. K.; Ganem, B. Tetrahedron Lett. 1995, 36, 8905. (d) Hansel,

J .-G.; O’Hogan, S.; Lensky, S.; Ritter, A. R.; Miller, M. J . Tetrahedron

Lett. 1995, 36, 2913 (e) Zhang, D.; Ghosh, A.; Su¨ling, C.; Miller, M. J .

Tetrahedron Lett. 1996, 37, 3799. (f) Vogt, P. F.; Hansel, J .-G.; Miller,

M. J . Tetrahedron Lett. 1997, 38, 2803.

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Tetrahedron: Asymmetry 1994, 5, 1019. (b) Farr, R. A.; Peet, N. P.;

Kang, M. S. Tetrahedron Lett. 1990, 31, 7109.

(20) (a) Griffith, D. A.; Danishefsky, S. J . J . Am. Chem. Soc. 1991,

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37, 599. (c) Taylor, S. J .; McCague, R.; Wisdon, R.; Lee, C.; Dickson,

K.; Ruecroft, G.; O’Brien, F.; Littlechild, J .; Bevan, J .; Roberts, S. M.;

Evans, C. T. Tetrahedron: Asymmetry 1993, 4, 1117. (d) Cheˆnevert,

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115, 444. (b) Trost, B. M.; Stenkamp, D.; Pulley, S. R. Chem. Eur. J .

1995, 1, 568. (c) Trost, B. M.; Madsen, R.; Guile, S. D. Tetrahedron

Lett. 1997, 38, 1710.

(23) Moyano, A.; Charbonnier, F.; Greene, A. E. J . Org. Chem. 1987,

52, 2919-2922.

(24) Sola, L.; Castro, J .; Moyano, A.; Pericas, M. A.; Riera, A.

Tetrahedron Lett. 1992, 33, 2863.

(25) Denmark, S. E.; Kesler, B. S.; Moon, Y.-C. J . Org. Chem. 1992,

57, 4912.

(26) Dixon, J . A.; Seierstad, M.; Denmark, S. E. Acta Crystallogr.

C. Submitted.

(22) Ledford, B. E.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117,

11811.

(27) The recovered vinyl ether (-)-6 from the SnCl₄-promoted

cycloaddition, had isomerized to approximately 3/1 (trans/cis) ratio.

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6181

Ta ble 1. Asym m etr ic [4 + 2] Cycloa d d ition s w ith 8

a n d (-)-6

Sch em e 7

Lewis acid (equiv)

T, °C

yield, %

9a /9b/9c/9d ^a

Using a similar sequence of events as outlined above,

a 15/1 mixture of nitronates 9b and 9a (obtained from

an MAPh cycloaddition) was heated in benzene to afford

a 25/1 mixture of nitroso acetals 10b and 10a in 96%

yield. Unmasking of the nitroso acetals with nickel

boride provided a single amino diol (+)-11a in 72% yield

(along with a 94% recovery of (-)-4). The triacetate

SnCl₄(1)

MAPh (3)

-78

-25

93

95

32/2/0/1

1/15/1.8/0

a

Determined by isolation and by ¹H NMR integration.

the chiral vinyl ether and the nitroalkene.²⁹Therefore,

the overall diastereofacial selectivity of the cycloaddition

in the exo series is 15/1 (9a /9b).

Sch em e 8

In view of our previous observations on the influence

of Lewis acids on the stereochemical course of [4 + 2]

cycloaddition, we next examined the reaction of 8 with

(-)-6 promoted by MAPh.³⁰The diastereomeric nitro-

nates 9a , 9b, and 9c were formed in excellent yield (95%),

however this time in a ratio of 1/15/1.8, Table 1. Thus,

the reaction was again exo-(alkoxy) selective (exo/endo,

>8.8/1 (9a + 9b/9c), but remarkably, the major diaste-

reomer from the MAPh-promoted cycloaddition cor-

responded to the minor exo diastereomer obtained in the

SnCl₄-promoted cycloaddition. The use of Ti(O-i-Pr)₂Cl₂

as the Lewis acid promoter in the [4 + 2] cycloaddition

of 8 with (()-6 provided a complex mixture of several

diastereomeric nitronates.³¹

Intramolecular [3 + 2] cycloaddition of 9a (obtained

from the SnCl₄cycloaddition) in refluxing benzene pro-

vided the tricyclic nitroso acetal 10a as a crystalline solid

in quantitative yield. The full stereostructure of 10a was

secured through single-crystal X-ray analysis of (()-20a

that was obtained from a SnCl₄-promoted tandem cy-

cloaddition of nitroalkene 8 with enol ether (()-6.³²The

nitroso acetals were reduced in an improved procedure

with nickel boride³³(instead of the conventional Raney

nickel) to afford amino diol (-)-11a in 82% yield along

with 94% of the recovered alcohol (-)-4. To facilitate

purification and allow for the determination of enantio-

meric purity, the amino diol (-)-11a was peracylated to

provide the triacetate (+)-12a in 83% yield and >99%

enantiomeric excess (ee).³⁴

(-)-12a obtained from acylation of (+)-11a was found to

be of 93% ee but was levorotatory and thus belonged to

the opposite configurational series as the triacetate

derived from the SnCl₄-promoted tandem process. There-

fore, from a single, chiral, nonracemic auxiliary, either

enantiomer of the final amino diol can be obtained by

appropriate selection of the Lewis acid in the tandem

sequence.

Op tim iza tion of th e [4 + 2] Cycloa d d ition of 8

w ith (-)-6. During the investigation into the asym-

metric bridged-mode (â-tether) tandem process, we dis-

covered an unusual stoichiometry dependence on the

diastereoselectivity of the SnCl₄-promoted [4 + 2] cy-

cloaddition. In the reaction of nitro olefin 8 with vinyl

ether (-)-6, when 2 equiv of (-)-6 was added to a solution

of 1 equiv of SnCl₄and nitroalkene 8, a >30/1 (9a + 9b)/

(9c + 9d ) ratio of diastereomeric nitronates was obtained

in 96% yield, Table 2, entry 1. However, if only 1 equiv

of vinyl ether was added to a solution containing ni-

troalkene and 2 equiv of SnCl₄, then the diastereoselec-

tivity eroded to 5/1 (9a + 9b)/(9c + 9d ), entry 2. Since

the change in the reagent stoichiometry had such a

dramatic influence on the diastereoselectivity of the

reaction, other experiments were conducted to gain

insight into the origin of this dependence. In entries 3

and 4, the stoichiometry of the vinyl ether and SnCl₄

change relative to the amount of nitroalkene used in the

cycloaddition. Interestingly, this variation appears to

have a small effect on the diastereomeric ratio, 10/1 vs

>20/1 (9a + 9b)/(9c + 9d ), for these reactions.

(28) (a) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982,

21, 654. (b) For an excellent discussion of the stereochemical terminol-

ogy, see: Helmchen, G. In Stereoselective Synthesis, Methods of Organic

Chemistry (Houben-Weyl); Edition E21; Helmchen, G., Hoffman, R.,

Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 1, p 1.

(29) The topicity is defined at the â-carbons of the reactive compo-

nents.

(30) Methylaluminum bis(2,6-diphenylphenoxide). Maruoka, K.;

Yamamoto, H. Tetrahedron 1988, 44, 5001.

(31) Chiral vinyl ethers, derived from 2,2-diphenylcyclopentanol and

TCC, were explored in the [4 + 2] cycloaddition; however, they offered

no particular advantage with respect to their preparation, yield, and

selectivity.

(32) Dixon, J . A.; Swiss, K. A.; Denmark, S. E. Acta Crystallogr. C

52, 1996, 2561.

(33) For review on nickel boride see: Ganem, B.; Osby, J . O. Chem.

Rev. 1986, 86, 763.

(34) Determined by chiral stationary phase HPLC, see Supporting

Information for details.

The use of a substoichiometric amount of SnCl₄to

promote the [4 + 2] cycloaddition provided the diaster-

6182 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

Ta ble 2. Stoich iom etr y Dep en d en ce of

Dia ster eoselectivity in th e [4 + 2] Cycloa d d ition of 8

w ith (-)-6

Ta ble 3. Asym m etr ic [4 + 2] Cycloa d d ition s w ith 13

a n d (-)-6

ratio^a

Lewis acid (equiv)

T, °C

yield, %

14a /14b/14c/14d ^a

entry equiv, 6 equiv, SnCl₄yield, % (9a + 9b)/(9c + 9d )

SnCl₄(1)

MAPh (4)

-78

80

90

6.9/1/3.4/0

3/19/0/1

1

2

3

4

5

6

2

1

2

1

1^b

96

89

90

76

80

88

>30/1

5/1

10/1

>20/1

>30/1

0

2^b

Determined by isolation and by ¹H NMR integration.

a

2^b

1^b

0.5^b

1^c

omeric nitronates 14a , 14b, and 14d in excellent yield

(95%), Table 3. The nitronate 14d is assigned as having

a trans relationship between the C(4) and C(5) substit-

uents and thus may result from an exo-(allyl), endo-

(alkoxy) mode reaction. The overall exo/endo-(alkoxy)

selectivity of the cycloaddition is 22/1 (14b + 14a / 14d )

while the diastereofacial selectivity in the exo manifold

is 6.7/1 (14b/14a ). Once again, the major diastereomer

from the MAPh-promoted cycloaddition corresponded to

the minor exo-(alkoxy) diastereomer obtained in the

SnCl₄-promoted cycloaddition

a

b

Ratios were determined by ¹H NMR integration. Vinyl ether

was added to a solution of nitroalkene and SnCl₄. ^cSnCl₄was

added to a solution of nitroalkene and vinyl ether.

eomeric nitronates in good yield with high diastereose-

lectivity (>30 /1, (9a + 9b)/(9c + 9d )), entry 5. Last, by

changing the order of addition for this reaction (adding

the SnCl₄to a solution of vinyl ether and nitro olefin) a

high diastereomeric ratio (>30 /1, (9a + 9b)/(9c + 9d ))

could also be obtained for this reaction, entry 6. Overall

two trends may be visible from these experiments. First,

the use of 1 equiv or less of SnCl₄is necessary for good

selectivity in the cycloaddition. Second, the use of excess

vinyl ether (-)-6 provides greater yields for this reaction.

Cycloa d d ition s a n d Red u ction s of Nitr o Olefin 13

w ith Vin yl Eth er (-)-6. To investigate the generality

of the bridged-mode (â-tether) tandem process and the

Lewis acid dependent switch in diastereofacial selectivity,

nitroalkene 13²⁵was used as the 4π component in the

tandem process. The SnCl₄-promoted [4 + 2] cycloaddi-

tion of 13 with (-)-6 afforded a mixture of diastereomeric

nitronates 14a , 14b, and 14c (6.9/1/3.4) in 80% yield,

Table 3. All three nitronate 14a , 14b, and 14c possess

a cis relationship between the C(4)-phenyl and C(5)-allyl

substituents; however, only nitronates 14a and 14b re-

tain the trans relationship of the vinyl ether. The stereo-

structure of 14c was secured through X-ray analysis of

the resulting nitroso acetal 15c.²⁶Additionally, all three

nitronates were converted into the same aminocyclopen-

tane triacetate after [3 + 2] cycloaddition, reduction, and

protection (vide infra). Since nitronates 14a , 14b, and

14c have a cis configuration between C(4) and C(5), they

are believed to arise from an endo-(allyl), exo-(alkoxy)

mode cycloaddition. Again, the nitronic ester subunits

of 14a and 14b are enantiomorphic and arise from exo-

(alkoxy) mode cycloadditions from unlike (ul)²⁸combina-

tions of the diastereotopic faces of the chiral vinyl ether

and the nitroalkene.²⁹The all-cis relationship in 14c may

result from epimerization of the C(6) acetal center of 14a

under the reaction conditions. Interestingly, the cycload-

dition is completely exo selective with the overall dias-

tereofacial selectivity being 10.3/1 (14a + 14c/14b).

The MAPh-promoted [4 + 2] cycloaddition of 13 with

vinyl ether (-)-6 provided a 3/19/1 mixture of diastere-

Intramolecular [3 + 2] cycloaddition of 14a and 14c

in refluxing benzene provided the diastereomeric nitroso

acetals 15a and 15c in 88% and 94% yields, respectively

(Scheme 9), and the full stereostructure of 15c was

Sch em e 9

secured through single-crystal X-ray analysis.²⁶Nickel

boride reduction of nitroso acetals 15a and 15c provided

the same enantiomerically enriched amino diol (+)-16 in

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6183

53-82% yield. After acylation, the triacetate (+)-17 was

found to be enantiomerically enriched to the extent of

>95% ee.³⁴

The intramolecular dipolar cycloaddition of 14b was

effected by refluxing a dilute solution in benzene, to

provide the desired nitroso acetal 15b in 91% yield,

Scheme 10. Subsequent nickel boride reduction (96%)

Consequently, the mixtures of nitronates 20 and 21

were heated to effect the intramolecular dipolar cycload-

ditions affording a 25/1 mixture of diastereomeric nitroso

acetals 22a /b in 87% yield and intermediate nitroso

acetals 23 which were unstable to purification and were

used directly in the next reaction. Nickel boride reduc-

tion of the nitroso acetals 22a /b afforded the desired

amino diol 24 as 3/1 mixture of C(1) epimers in 82%

yield.³⁶Subsequent acylation of 24 provided triacetates

(-)-26a and 26b in 59% yield. The major epimer (-)-

26a was found to be of 95% ee.³¹Similarly, nickel boride

reduction of nitroso acetal 23 provided the desired amino

diol 25a in 61% yield over two steps. After acylation

(68%), the triacetate (-)-27a was found to be enriched

to the extent of >98% ee.³⁴

Sch em e 10

Cycloa d d ition s a n d Red u ction s of 8 a n d 19 w ith

Cis Vin yl Eth er (-)-7. To access a C(2) diastereomeric

amino diol using the bridged-mode tandem process, we

required either an endo-(alkoxy) selective [4 + 2] cycload-

dition using a trans vinyl ether or an exo-(alkoxy)

selective cycloaddition with a cis vinyl ether, Scheme 11.

followed by acylation afforded the triacetate (-)-17 in

73% yield and >95% ee. Again, from a single, enan-

tiopure auxiliary, either enantiomer of the final amino

diol can be obtained by appropriate selection of the Lewis

acid in the tandem sequence.

Sch em e 11

Cycloa d d ition s a n d Red u ction s of Nitr oa lk en es

18 a n d 19 w ith (-)-6. To further probe the generality

of the bridged-mode tandem [4 + 2]/[3 + 2] reaction, trans

2-substituted nitro olefins containing aromatic and het-

eroatom substituents were tested in the reaction se-

quence. MAPh was chosen as the Lewis acid for these

reactions since it promotes highly selective cycloadditions

and is a relatively mild reagent. Thus, the [4 + 2]

cycloadditions of 18²⁵and 19³⁵with (-)-6 afforded

mixtures of nitronates 20 and 21 in good to excellent

yields (68-92%), Table 4. In both cases the major

Since most of the asymmetric [4 + 2] cycloadditions in

the bridged-mode series are highly exo selective, we chose

to investigate the use of cis vinyl ethers as the dienophile/

dipolarophile component.

The SnCl₄-promoted [4 + 2] cycloaddition of nitroal-

kene 8 with cis vinyl ether (-)-7 afforded a 11/1 mixture

of diastereomeric nitronates 9d and 9e in excellent yield

(93%), Table 5.³⁷Diastereomers 9d and 9e possess a

Ta ble 5. Asym m etr ic [4 + 2] Cycloa d d ition s w ith 8

a n d (-)-7

Ta ble 4. Ta n d em [4 + 2]/[3 + 2] Cycloa d d ition a n d

Red u ction Sequ en ce

Lewis acid (equiv)

T, °C

yield, %

9d /9e^a

SnCl₄(1)

MAPh (3)

-78

-30

93

70

11/1

1/8

a

Determined by isolation and by ¹H NMR integration.

trans relationship between the C(4)-phenyl and C(5)-allyl

substituents and retain the cis relationship of the vinyl

ether. Thus, they must arise from endo-(allyl), exo-

(alkoxy) mode cycloadditions. Interestingly, the major

nitronate 9d obtained from this reaction corresponded

to a minor diastereomer found in the SnCl₄-promoted [4

+ 2] cycloaddition of 8 with trans vinyl ether (-)-6. The

stereostructural assignment of the nitronate 9e was

made by analogy to the cycloadditions of the trans vinyl

ether series and was later confirmed by X-ray analysis

of nitroso acetal 10e. Overall, the cycloaddition is

nitroalkene nitronate nitroso acetal amino diol

triacetate

(R¹)

yield,^a

%

yield, % (dr)

yield, %

yield, % (ee, %)^d

18 (Ph)

19 (OBz)

20 92

21 68

22 87 (25/1)

23 - (nd)

24 82^b

(-)-26 59^b(95)^e

(-)-27a 68 (>98)

25a 61^c

a

b

Isolated as a mixture of diastereomers. Isolated as 3.5:1

mixture of epimeric amino diols at C(1). ^cYield over two steps.

Determined by CSP HPLC. ^eee of major isomer 26a .

d

nitronate is believed to have arisen from an endo-(allyl),

exo-(alkoxy) mode cycloaddition; however, the exact dia-

stereomeric ratios could not be determined at this stage

due to the propensity of the nitronates to slowly undergo

[3 + 2] cycloaddition at room temperature.

(36) Epimeric ratios ranging from 3.5 to 20/1 have been obtained

for this reaction.

(37) The recovered vinyl ether (-)-7 from the SnCl₄-promoted

cycloaddition had isomerized to an approximately 1.4/1 (cis/trans) ratio.

(35) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1994, 59, 5672.

6184 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

Sch em e 14

completely exo selective with the diastereofacial selectiv-

ity being 11/1 (9d /9e).

The MAPh-promoted [4 + 2] cycloaddition of 8 with

enol ether (-)-7 again provided a mixture of nitronates

9d and 9e now in a ratio of 1/8 (9d /9e) in 70% yield, Table

5. The major diastereomer from the MAPh-promoted

cycloaddition corresponded to the minor diastereomer

obtained in the SnCl₄-promoted cycloaddition.

Intramolecular [3 + 2] cycloaddition of 9d in refluxing

toluene provided the tricyclic nitroso acetal 10d in 93%

yield, Scheme 12. Reduction of nitroso acetal 10d using

Sch em e 12

major nitronate 28a is believed to have arisen from an

exo-(alkoxy) mode cycloaddition; however, the precise

diastereomeric ratio for this cycloaddition could not be

determined due to difficulties in removing small amounts

of decomposed products. The intramolecular [3 + 2]

cycloaddition of 28 did not proceed as readily as for the

trans vinyl ether series. Higher temperatures and/or

longer reaction times were necessary to effect the [3 +

2] cycloaddition, which in turn caused considerable

decomposition.³⁹Nonetheless, the unstable nitroso acetal

29 could be directly subjected to nickel boride reduction.

Subsequent acylation of amino diol 30 provided the

desired triacetate (+)-31 in 16% yield (over three steps)

and in >98% ee.³⁴

nickel boride afforded the amino diol (-)-11b in 83% yield

along with 94% of the recovered alcohol (-)-4. Subse-

quent acetylation of (-)-11b generated the triacetate (-)-

12b in 73% yield. The extent of enantiomeric purity of

(-)-12b was determined to be 95% ee.³⁸

Nitronate 9e was smoothly transformed in refluxing

toluene into the desired nitroso acetal 10e in 86% yield,

Scheme 13. The full stereostructure of 10e was secured

Discu ssion ⁴⁰

Asym m etr ic [4 + 2] Cycloa d d ition s. From the

analysis of previous asymmetric tandem nitroalkene

cycloadditions, two principle factors have been identified

that govern the stereochemical course of the reaction.²

The first factor involves the orientation (exo or endo) of

the chiral vinyl ether in its approach to the nitroalkene.

This feature determines the relative topicity of the

reacting termini and establishes the stereochemical

relationship between C(4) and C(5) (and de facto, C(4)

and C(6)). The second factor entails the stereodifferen-

tiation of the chiral vinyl ether for one π-face (si or re) of

the nitroalkene.⁴¹This component governs the relative

topicity of the C(5) (and de facto C(6)) center with respect

to the chiral auxiliary, i.e., the absolute configurational

series of the final aminocyclopentanedimethanol. For the

purposes of this analysis these factors will be discussed

individually; however, they are in actuality highly inter-

dependent.

To facilitate the following discussion, some important

stereochemical information is outlined in Figure 2. The

prochiral descriptors are uniquely defined at the reacting

components as follows: at the 2-position of the 1-nitro-

alkene and the C(3) and C(4) positions of the vinyl ether.

Reaction of the C(4) si face of the vinyl ether with the re

face of the nitro olefin would result in an unlike combina-

tion and is designated as ul. Alternatively, if the reaction

took place on the C(4) re face of a vinyl ether with the re

face of the nitroalkene, then that combination would be

Sch em e 13

through single-crystal X-ray analysis²⁶of (()-10e gener-

ated from a MAPh-promoted tandem sequence. Unmask-

ing of the nitroso acetal with nickel boride provided

amino diol (+)-11b in 81% yield (along with a 92%

recovery of (-)-4). The triacetate (+)-12b, obtained from

acylation of (+)-11b, was found to be >98% ee.³⁸Again,

the triacetate from this sequence belonged to the opposite

enantiomeric series as the triacetate resulting from the

SnCl₄-promoted tandem process.

To incorporate additional oxygen functionality into this

amino diol series, we chose to examine the asymmetric

[4 + 2] cycloaddition of nitro olefin 19 with the cis-enol

ether (-)-7. The MAPh-promoted [4 + 2] cycloaddition

of 19 with (-)-7 produced a mixture of somewhat

unstable nitronates 28 in 60% yield, Scheme 14. The

(39) Various solvent and temperatures were tried to optimize the

yield and minimize decompostion of this reaction.

(40) A detailed discussion of the [3 + 2] cycloaddition and nitroso

acetal stability as well as the mechanism of hydrogenolysis can be

found in the preceding paper.

(38) Determined by chiral stationary phase supercritical fluid

chromotography (SFC), see Supporting Information for details.

(41) The re and si faces are defined at the â-carbon atom of the

niroalkene.

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6185

respect to the nitro olefin in the [4 + 2] cycloaddition (i.e.,

ul topicity). Moreover, since the relative configuration

of the auxiliary ((1R*,2S*)-2-phenylcyclohexanol) is known,

the relative configurations of C(4) and C(5) in 9a can be

assigned as 4R*,5R*. To obtain the 4R*,5R* configura-

tion, the C(3) re face of the enol ether 6 must approach

the re face of the nitroalkene 8. This approach would

necessitate 1,3-lk induction (i.e., 1R auxiliary, re face vin-

yl ether). Previous analysis of molecular and computa-

tional models revealed that the C(3) re face of trans vinyl

ethers derived from (1R,2S)-4 are most accessible in the

limiting s-cis reactive conformation, Figure 3. Moreover,

the difference in ground-state energies of the s-cis and

s-trans conformations was found to be negligible. Ad-

ditionally, the preference for the vinyl ether to react in a

s-cis conformation by an exo approach appears to be a

general characteristic for SnCl₄-promoted reactions.^2g,3

The MAPh-promoted cycloaddition of nitro olefin 8

with vinyl ether (-)-6 afforded 9b as the major nitronate,

which bore a C(4)/C(5) cis, C(5)/C(6) trans relationship

and therefore also arose from an endo-(allyl), exo-(alkoxy)

[4 + 2] cycloaddition (ul topicity). However, this nitro-

nate belongs to the opposite configurational family as 9a

(as evidenced by its ultimate conversion to (-)-12a ).

Therefore, 9b must arise from the combination of the C(3)

si face of (-)-6 with the si face of 8 (i.e., 1,3-ul induction,

1R auxiliary, si face vinyl ether). To accommodate this

pairwise combination, the vinyl ether (1R,2S)-6 must

react via the s-trans conformation as depicted in Figure

4. It has been well established that MAPh promotes

predominately exo-(alkoxy) mode, s-trans cycloadditions,

presumably due to the size of this bulky Lewis acid.²

The influence of the Lewis acid on the stereochemical

outcome of the asymmetric [4 + 2] cycloaddition of nitro

olefins and chiral vinyl ethers has been well docu-

mented.^2a-c,gThe Lewis acid-dependent reversal of ste-

reoselectivity observed between Ti(O-i-Pr)₂Cl₂and MAPh

in the fused mode tandem process has been attributed

to a switch in the relative topicity (endo/exo) of the vinyl

ether and the Lewis acid-nitroalkene complex.^2b,cIn

both of these cases, the relative sense of asymmetric

induction at the chiral vinyl ether is the same. In the

current study, we have discovered a new mode of Lewis

acid-dependent stereoselection, which preserves the rela-

tive topicity of the reactive partners but alters the sense

of asymmetric induction at the chiral vinyl ether. At this

F igu r e 2. Stereochemical definitions in asymmetric [4 + 2]

cycloaddition.

termed like (lk). A second stereochemical component to

this definition involves the asymmetric induction of the

chiral auxiliary. In this case, the configuration of the

auxiliary at C(1) is compared to the prochiral descriptor

of the olefin at C(3). For example, if the (1R,2S)-phenyl-

cyclohexanol-derived vinyl ether (-)-6 reacts at the (C(3))

si face, then the relative induction would be denoted as

1,3-ul (1R of the auxiliary with the si face of the olefin).

From consideration of the these factors, unified models

have been developed to rationalize the stereochemical

course of Lewis acid-promoted [4 + 2] cycloadditions

involving both the trans vinyl ether (-)-6 and cis vinyl

ether (-)-7. The reactive conformation of the vinyl ether

(-)-6 in the SnCl₄-promoted [4 + 2] cycloaddition with

nitroalkene 8 can be inferred through analysis of the

X-ray crystal structure of nitroso acetal (()-10a . The

structure of (()-10a would uniquely arise from a cis

relationship between the phenyl (C(4)) and the allyl group

(C(5)) in nitronate 9a , which can only be established by

an endo-mode orientation of the allyl appendage with

F igu r e 3. Proposed model of the SnCl₄-promoted asymmetric [4 + 2] cycloaddition.

6186 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

F igu r e 4. Proposed model of the MAPh-promoted asymmetric [4 + 2] cycloaddition.

F igu r e 5. Approach of vinyl ether (-)-6 in an s-trans

conformation to the SnCl₄•8 complex.

F igu r e 6. Approach of vinyl ether (-)-6 in an s-cis conforma-

tion to the SnCl₄•8 complex.

time, a clear understanding for the change in vinyl ether

conformation with the two different reagents is lacking

primarily due to the paucity of structural information on

the nitroalkene/Lewis acid complexes. However, one

plausible explanation may involve the sensitivity of the

enol ether geometry to the steric environment of the

different Lewis acid-nitroalkene complexes. It has been

concluded that when MAPh and Ti(O-i-Pr)₂Cl₂are used

to promote nitroalkene [4 + 2] cycloadditions, the vinyl

ether prefers to react in an s-trans conformation (1,3-

ul).^2b,cAlternatively, it appears that when SnCl₄is used

as the promoter, the vinyl ether prefers to react through

an s-cis orientation (1,3-lk). We suspect that the switch

from a s-trans to the s-cis reactive conformation may be

attributed to nonbonding interactions of the approaching

enol ether with a SnCl₄-nitroalkene complex. Models

of the two limiting conformations (s-trans and s-cis) of

the vinyl ether (-)-6 with the SnCl₄-8 complex are

shown in Figures 5 and 6.⁴²The tin atom is postulated

to be hexacoordinate having another nitro olefin, product

nitronate, or vinyl ether as the sixth ligand (the sixth

ligand on tin in Figures 5 and 6 is depicted as methanol

for simplicity). We assume that tin is octahedrally

disposed since SnCl₄is most commonly found in the

hexacoordinate state when complexed with basic ligands.⁴³

Shown in Figure 5 is the approach of vinyl ether (-)-6

(in an s-trans conformation) to the SnCl₄•8 complex. In

this orientation, the methine hydrogen of the auxiliary

appears to experience severe nonbonding interactions

with one of the chlorine atoms of the Lewis acid.

However, if the vinyl ether adopts an s-cis conformation,

then the steric interactions are relieved, Figure 6.

This rationale can be used to explain the stereochem-

ical outcome of the [4 + 2] cycloadditions of nitronate 8

with the cis vinyl ether (-)-7. Again, in the SnCl₄-

promoted cycloaddition, the enol ether (-)-7 is believed

to react through an s-cis conformation in an exo-(alkoxy)

mode approach to the nitro olefin. In the MAPh-

promoted reaction, the vinyl ether is believed to adopt

an s-trans orientation as it approaches the nitroalkene/

MAPh complex in an exo fashion.

Stoich iom etr y Stu d ies. During the optimization of

the SnCl₄-promoted [4 + 2] cycloaddition of 8 with (-)-

6, it was noticed that diastereoselectivity eroded when

more than 1 equiv of SnCl₄was added. In particular,

the amount of 9d increased as the concentration of SnCl₄

increased, while the amount of diastereomer 9c that was

produced remained virtually unchanged. The most likely

explanation for this observation is that 9d is not a result

of an endo-mode cycloaddition of 8 and vinyl ether (-)-6

which is followed by epimerization of C(6) but from an

exo-mode cycloaddition of the cis vinyl ether (-)-7,

Scheme 15.

(42) The models were constructed using modified X-ray crystal-

lographic data from Lewis, F. D.; Oxman, J . D.; Huffman, J . C. J . Am.

Chem. Soc., 1984, 106, 466.

(43) (a) Satchell, D. P. N.; Wardell, J . P. Proc. Chem. Soc. 1963, 86.

(b) Dumas, J . M.; Gomel, M. Bull. Chem. Soc. Fr. 1974, 1885. (c)

Merbach, A. E.; Knight, C. T. G. Inorg. Chem. 1985, 24, 576.

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6187

Sch em e 15

tiomerically enriched trans- and cis-1-alkoxy-1,4-penta-

dienes serve admirably as the dienophile/dipolarophile

components in the bridged-mode (â-tether) sequence. A

variety of nitroalkenes, including mono- and disubsti-

tuted as well as oxygen functionalized substrates, par-

ticipate in the sequence, affording intermediate nitro-

nates and nitroso acetals in good yields and high dia-

stereoselectivities. Hydrogenolysis of the nitroso acetals

provides goods yields of highly enantiomerically enriched

aminocyclopentanes. Importantly, by changing the Lewis

acid from SnCl₄to MAPh in the tandem sequence,

enantiomeric amino diols can be obtained using a single

enantiomer of the chiral vinyl ether. Further studies on

the application of this process toward the synthesis of

aminocyclopentanoid natural products are in progress.

In the presence of SnCl₄, the trans vinyl ether 6 was

observed to partially isomerize to the cis vinyl ether 7.

This was discovered when unreacted vinyl ether (-)-6

was recovered from the SnCl₄-promoted cycloaddition and

it was found to have isomerized to a 3/1 (6/7) ratio. An

exo-mode [4 + 2] cycloaddition of enol ether 7 gives rise

to the requisite nitronate 9d . Thus, if more than 1 equiv

of SnCl₄is used in the reaction, there is likely to be a

greater propensity for the trans isomer 6 to isomerize to

the cis derivative 7, leading to increased production of

diastereomeric nitronate 9d .

Hyd r ogen olysis. The suggested mechanism for the

nickel boride reduction of the nitroso acetals to the

corresponding amino diols is similar to the mechanism

proposed for the Raney nickel and sodium borohydride

reduction of the achiral nitroso acetals (see the preceding

paper).³A plausible explanation for the formation of

epimeric C(1) amino diols 24 from the reduction of nitroso

acetal 22 is outlined in Scheme 16. Deprotonation of

Exp er im en ta l Section

Gen er a l. See Supporting Information.

Ma ter ia ls. See Supporting Information.

1-[(1R,2S)-(2-P h en ylcycloh exyl)oxy]pen t-4-en -1-yn e (5).

A solution of (-)-(1R,2S)-phenylcyclohexanol ((-)-4) (3.84 g,

22.2 mmol, 1.0 equiv, >99% ee) in THF (39 mL) was added to

a suspension of prewashed (5 × 10 mL of hexanes) potassium

hydride (1.87 g, 46.62 mmol, 2.1 equiv) in THF (39 mL) at room

temperature. Hydrogen evolution was observed, and the

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

potassium alkoxide was then cooled to -78 °C, and a solution

of trichloroethylene (2.78 mL, 23.31 mmol, 1.1 equiv) in THF

(26 mL) was added via cannula. After the addition was

complete, the mixture was immediately warmed to room

temperature and was stirred for 13 h. The resulting dark

mixture was cooled to -78 °C, and n-butyllithium (41.0 mL,

53.3 mmol, 2.4 equiv) was added slowly via cannula and was

warmed slowly to 0 °C over a period of 2.5 h. The mixture

was stirred for an additional 30 min at 0 °C and was then

recooled to -78 °C. A solution of allyl iodide (6.0 mL, 66.6

mmol, 3 equiv) in HMPA (10 mL) was added via cannula to

the cold reaction mixture and was stirred betweeen -70 and

-50 °C for 1 h. After being warmed to 0 °C and stirring at

that temperature for 3 h, the mixture was quenched with a

saturated ammonium chloride solution (50 mL). The mixture

was diluted with pentane (100 mL) and was washed with

water (3 × 75 mL). The aqueous phase was back-extracted

with pentane (3 × 75 mL), and the combined organic phases

were washed with brine (100 mL), dried (Na₂SO₄), and filtered

through a pad of basic alumina activity III, washing with

pentane (100 mL). Concentration of the filtrate afforded a

brown oil which was purified by column chromatography (basic

alumina (III), pentane) to provide 4.42 g (83%) of a 20:1

mixture of (-)-5 to [(1R,2S)-(2-phenylcyclohexyl)oxy]ethyne as

a light yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.31 (m,

2 H), 7.26-7.22 (m, 3 H) 5.80 (ddt, J ) 15.6, 10.2, 5.1, 1 H),

5.25 (dq, J ) 17.2, 1.8, 1 H), 5.04 (dq, J ) 10.2, 1.6, 1 H), 4.05

(td, J ) 10.8, 4.4, 1 H), 2.86 (dt, J ) 5.1, 1.8, 2 H), 2.78-2.73

(m, 1 H), 2.45-2.41 (m, 1 H) 1.96-1.91 (m, 2 H), 1.78-1.75

(m, 1 H), 1.68-1.60 (m, 1 H), 1.57-1.30 (m, 3 H); ¹³C NMR

(125.6 MHz, CDCl₃) δ 142.71, 134.48, 128.39, 127.54, 126.58,

114.90, 89.58, 88.66, 49.01, 35.37, 33.84, 30.97, 25.55, 24.69,

21.78; IR (CHCl₃) 2940, 2268; MS (FAB) 241 (M⁺+ 1, 4), 159

Sch em e 16

nitroso acetal 22, with concomitant â-alkoxy elimination

under the mildly basic reaction conditions (i.e., NaB-

(OMe)₄), could provide the dihydroisoxazole intermediate

i. This intermediate may subsequently undergo a N-O

bond cleavage and breakdown of the hemiacetal, to

provide the imino aldehyde ii. Reduction of the aldehyde

followed by the unselective saturation of the imine

provides the C(1) epimeric amino diols 24. Alternatively,

single N-O bond cleavage may occur prior to deproto-

nation and reduction.

(100); TLC R_f0.38 (hexane/EtOAc, 20/1); optical rotation [R]²⁵

D

) -66.8° (c ) 1.1, CHCl₃); HRMS (FAB) calcd for C₁₇H₂₀

O

241.15924, found 241.15900.

tr a n s-1-[(1R,2S)-(2-P h en ylcycloh exyl)oxy]-1,4-p en ta d i-

en e ((-)-6). Lithium aluminum hydride (2.8 g, 72.52 mmol,

4 equiv) was added to a solution of the acetylenic ether (-)-5

(4.36 g, 18.13 mmol) in THF (180 mL). The suspension was

heated to reflux for 1.5 h. After the solution was cooled to

room temperature, the excess hydride was quenched with

water (2.9 mL), 15% NaOH/H₂O (2.9 mL), and finally water

(5.8 mL). The suspension was stirred at room temperature

Con clu sion

An asymmetric variant of the tandem [4 + 2]/[3 + 2]

cycloaddition process has been developed which provides

access to highly substituted aminocyclopentanes. Enan-

6188 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

for ca. 30 min, and the white salts were removed by filtration,

washing with EtOAc (100 mL). Concentration of the filtrate

afforded a light yellow oil, which was purified by silica gel

column chromatography (10:1 hexane/benzene) to provide 1.57

g of analytically pure vinyl ether (-)-6 and 2.16 g of a 16:1

mixture of (-)-6 to [(1R,2S)-2-(phenylcyclohexyl)oxy]ethene

(85% yield overall): ¹H NMR (499.7 MHz, CDCl₃) δ 7.30-7.26

(m, 2 H), 7.21-7.17 (m, 3 H) 5.82 (d, J ) 12.4, 1 H), 5.72-

5.64 (m, 1 H), 4.94-4.87 (m, 2 H), 4.67 (dt, J ) 12.3, 7.1, 1 H),

3.73 (td, J ) 10.2, 4.4, 1 H), 2.63 (ddd, J ) 12.4, 10.4, 3.8, 1

H), 2.48 (td, J ) 7.3, 1.3, 2 H), 2.24-2.18 (m, 1 H), 1.93-1.83

(m, 2 H) 1.77-1.73 (m, 1 H), 1.54-1.46 (m, 1 H), 1.43-1.29

(m, 3 H); ¹³C NMR (125.6 MHz, CDCl₃) δ 146.25, 143.84,

138.09, 128.22, 127.66, 126.19, 114.28, 102.89, 82.30, 50.43,

34.07, 32.33, 31.63, 25.87, 24.84; IR (neat) 2931, 1670, 1121;

MS (CI, CH₄) 243 (M⁺+ 1, 11), 159 (100); TLC R_f0.39 (hexane/

EtOAc, 20/1); optical rotation [R]²⁴_D) -16.1° (c ) 1.3, CHCl₃).

Anal. Calcd for C₁₇H₂₂O (242.364): C, 84.25; H, 9.15.

Found: C, 84.22; H, 9.22.

cis-1-[(1R,2S)-(2-P h en ylcycloh exyl)oxy]-1,4-p en t a d i-

en e ((-)-7). A solution of acetylenic ether (-)-5 (2.5 g, 10.4

mmol) in THF (20 mL) was added to a solution of diisobutyl-

aluminum hydride (5.56 mL, 31.2 mmol, 3 equiv) in THF (70

mL). The reaction mixture was heated to reflux for 1.5 h. After

the solution was cool to room temperature, the reaction was

quenched with an aqueous solution of sodium potassium

tartrate (20 mL). The gelatinous mixture was stirred at room

temperature for ca. 3 h. The mixture was diluted with EtOAc

(100 mL) and washed with water (3 × 50 mL). The aqueous

phase was back-extracted with EtOAc (3 × 50 mL), and the

combined orgainc layers were washed with brine (75 mL),

dried (MgSO₄), filtered, and concentrated to afforded a yellow

oil. Purification by silica gel column chromatography (hexane/

benzene, 13/1) provided 2.02 g of analytically pure vinyl ether

(-)-7 in 80% yield as a clear oil: ¹H NMR (499.7 MHz, CDCl₃)

δ 7.30-7.26 (m, 2 H), 7.23-7.17 (m, 3 H) 5.80-5.78 (m, 1 H),

5.67-5.59 (m, 1 H), 4.90-4.82 (m, 2 H), 4.14-4.09 (m, 1 H),

3.61 (td, J ) 10.0, 4.2, 1 H), 2.67-2.54 (m, 3 H), 2.17-2.14

(m, 1 H), 1.93-1.87 (m, 2 H) 1.78-1.76 (m, 1 H), 1.59-1.51

(m, 1 H), 1.49-1.31 (m, 3 H); ¹³C NMR (125.6 MHz, CDCl₃) δ

144.34, 143.82, 137.74, 128.12, 127.79, 126.17, 113.66, 103.46,

84.02, 50.48, 33.46, 32.85, 38.22, 25.81, 24.90; IR (neat) 2931,

1661, 1102; MS (CI, CH₄) 243 (M⁺+ 1, 2), 159 (100); TLC R_f

0.18 (hexane/benzene, 10/1); optical rotation [R]²²_D) -141.16°

(c ) 0.93, CHCl₃). Anal. Calcd for C₁₇H₂₂O (242.364): C,

84.25; H, 9.15. Found: C, 84.10; H, 9.06.

1.6, 1 H), 5.27-5.19 (m, 1 H), 4.93 (d, J ) 17.0, 1 H), 4.86 (d,

J ) 10.1, 1 H), 4.32 (td, J ) 10.2, 4.0, 1 H), 3.63 (dd, J ) 6.8,

1.5, 1 H), 2.57 (ddd, J ) 12.4, 10.6, 3.7, 1 H), 2.18-2.15 (m, 1

H), 2.02-1.95 (m, 1 H), 1.77-1.68 (m, 2 H), 1.62-1.56 (m, 1

H) 1.52-1.49 (m, 4 H), 1.45-1.41 (m, 1 H), 1.36-1.27 (m, 1

H), 1.11-0.98 (m, 3 H); ¹³C NMR (125.6 MHz, C₆D₆) δ 144.62,

137.68, 135.72, 129.53, 128.65, 128.29, 128.04, 127.16, 126.27,

118.37, 117.63, 97.03, 75.96, 51.35, 44.39, 38.98, 34.81, 32.25,

30.34, 26.24, 24.50, 18.19; IR (CHCl₃) 3012, 2939, 1232; MS

(FAB) 406 (M⁺+ 1, 100); TLC R_f0.33 (hexane/EtOAc, 2/1);

optical rotation [R]²³_D) -220.6° (c ) 1.0, CHCl₃). Anal. Calcd

for C₂₆H₃₁NO₃(405.534): C, 77.01; H, 7.71; N, 3.45. Found:

C, 77.06; H, 7.72; N, 3.48.

(4R,5S,6R)-3-Meth yl-4-ph en yl-5-(2-pr open yl)-6-[(1R,2S)-

(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H -[1,2]-oxa zin e

2-Oxid e (9d ). According to general procedure 1, tin tetra-

chloride (0.47 mL, 4.0 mmol, 2 equiv) was added to a -78 °C

solution of nitroalkene 8 (326 mg, 2.0 mmol) in CH₂Cl₂(15

mL) and the resulting complex was left to stir for 15 min. A

solution of vinyl ether (-)-6 (605 mg, 2.5 mmol, 1.5 equiv) in

CH₂Cl₂(5 mL) was added slowly dropwise to the cold reaction

mixture via syringe. The reaction was left to stir at -78 °C

for an additional 10 min and was then quenched with 1 N

NaOH/MeOH (5 mL). After an aqueous extractive workup,

the crude organic concentrate was purified by silica gel column

chromatography (hexane/EtOAc, 6/1 (700 mL), 5/1) to afford

0.572 g of 9a as a 13:1 (9a :9b) mixture by ¹H NMR integration,

125 mg of 9d , and 0.080 g of a mixure of 9c and 9d . The

overall yield of the reaction was 777 mg (96%) with a ratio of

3/1 for (9a + 9b)/(9c + 9d )). An analytical sample of 9d was

obtained by recrystallization (hexane). Nitronates 9a , 9b, and

9c were found to be identical by ¹H NMR to the nitronates

obtained from the previous SnCl₄reaction and the MAPh-

promoted [4 + 2] cycloadditions. Data for 9d : mp 104-105

1

°C (hexane); H NMR (400 MHz, C₆D₆) δ 7.35-7.29 (m, 4 H),

7.05-7.01 (m, 1 H), 6.94-6.92 (m, 3 H) 6.58-6.56 (m, 2 H),

5.33 (d, J ) 1.5, 1 H), 5.29-5.19 (m, 1 H), 4.86 (dd, J ) 19.2,

10.8, 2 H), 4.30 (td, J ) 10.3, 3.9, 1 H), 2.76 (d, J ) 9.0, 1 H),

2.52 (td, J ) 13.1, 3.5, 1 H), 2.11-2.07 (m, 1 H), 1.92-1.81

(m, 3 H), 1.73-1.68 (m, 1 H), 1.56-1.53 (m, 1 H) 1.46-1.44

(m, 1 H), 1.37-1.27 (m, 4 H), 1.12-0.94 (m, 3 H); ¹³C NMR

(100.6 MHz, C₆D₆) δ 144.61, 140.18, 134.88, 129.00, 128.80,

128.62, 128.04, 127.49, 126.21, 118.82, 117.49, 96.07, 75.60,

51.38, 46.63, 42.13, 34.85, 33.41, 30.39, 26.30, 24.54, 17.52;

IR (CHCl₃) 2938, 1619, 1232, 895; MS (FAB) 406 (M⁺+ 1, 99),

159 (100); TLC R_f0.26 (hexane/EtOAc, 2/1); optical rotation

Gen er a l P r oced u r e for Sn Cl₄-P r om oted [4 + 2] Cy-

cloa d d ition s (Gen er a l P r oced u r e I). The preparation of

9a from 8 will serve to illustrate the general procedure utilized.

(4R,5R,6R)-3-Meth yl-4-ph en yl-5-(2-pr open yl)-6-[(1R,2S)-

(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H -[1,2]-oxa zin e

2-Oxid e (9a ). Tin tetrachloride (0.13 mL, 1.09 mmol, 1 equiv)

was added to a -78 °C solution of nitroalkene 8 (179 mg, 1.09

mmol) in CH₂Cl₂(10 mL), and the resulting bright yellow

complex was left to stir for 15 min. A solution of vinyl ether

(-)-6 (525 mg, 2.17 mmol, 2.0 equiv) in CH₂Cl₂(2 mL) was

added rapidly to the cold reaction mixture via syringe, and

the yellow color faded as the vinyl ether was added. The

reaction was left to stir at -78 °C for an additional 5 min and

was then quenched with 1 N NaOH/MeOH (4 mL). The

mixture was diluted with CH₂Cl₂(150 mL) and washed with

water (3 × 100 mL). The aqueous phase was back-extracted

with CH₂Cl₂(3 × 50 mL), and the combined organic layers

were washed with brine (75 mL), dried (Na₂SO₄), and concen-

trated. The crude organic concentrate was purified by silica

gel column chromatography (hexane/EtOAc, 5/1 (600 mL), 4/1)

[R]²⁵) -337.8° (c ) 1.0, CHCl₃). Anal. Calcd for C₂₆H₃₁

-

D

NO₃(405.534): C, 77.01; H, 7.71; N, 3.45. Found: C, 77.15;

H, 7.74; N, 3.63.

Gen er a l P r oced u r e for MAP h -P r om oted [4 + 2] Cy-

cloa d d ition s (Gen er a l P r oced u r e II). The preparation of

9b from 8 will serve to illustrate the general procedure utilized.

(4S,5S,6S)-3-Meth yl-4-p h en yl-5-(2-pr open yl)-6-[(1R,2S)-

(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H -[1,2]-oxa zin e

2-Oxid e (9b). Trimethylaluminum (2.0 M in toluene, 1.7 mL,

3.40 mmol, 2.0 equiv) was added dropwise to a solution of 2,6-

diphenylphenol (1.67 g, 6.8 mmol, 4.0 equiv) in CH₂Cl₂(12 mL)

at room temperature. Gas evolution (CH₄) was observed as

the resulting light yellow solution stirred at room temperature

for 40 min. The Lewis acid solution (MAPh) was transferred,

via cannula, to a second reaction vessel containing a -78 °C

solution of nitroalkene 8 (277 mg, 1.7 mmol) and vinyl ether

(-)-16 (751 mg, 3.09 mmol, 1.8 equiv) in CH₂Cl₂(5 mL). The

resulting, dark brown solution was allowed to warm slowly to

-25 °C over a period of 1 h and was then left to stir at -25 °C

for 4 h (the color faded to a light brown), after which time the

reaction was quenched with H₂O (8 mL). The mixture was

diluted with CH₂Cl₂(150 mL) and washed with water (3 ×

100 mL). The aquous layers were back-extracted with CH₂-

Cl₂(3 × 50 mL), and the combined organic phases were washed

with brine (75 mL), dried (NaSO₄), filtered, and concentrated

in vacuo. The crude material was purified by silica gel column

chromatography (hexane/EtOAc, 6/1 (700 mL), 5/1 (600 mL),

4/1) and radial chromotography (hexane/EtOAc, 5/1) of mixed

fractions obtained in the column chromatography to afford 590

1

to afford 401 mg of 9a as a 15:1 (9a :9b) mixture by H NMR

integration and 12 mg of nitronate diastereomers 9c and 9d .

An analytical sample of 9a was obtained after recrystallization

(hexane/TBME) to afford a white crystalline solid. Nitronate

9b was found to be identical by ¹H NMR to the major nitronate

9b obtained from a MAPh-promoted [4 + 2] cycloaddition. Data

for 9a : mp 126-127 °C (TBME/hexane); ¹H NMR (499.7 MHz,

C₆D₆) δ 7.35-7.33 (m, 2 H), 7.30-7.27 (m, 2 H), 7.02-6.98

(m, 1 H) 6.94-6.92 (m, 3 H), 6.56-6.54 (m, 2 H), 5.51 (d, J )

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6189

mg of nitronates 9b and 9a and 67 mg of 9c. The ratio of

diastereomeric nitronates 9b, 9a , and 9c was found to be 15/

1/1.8 (9b/9a /9c) overall by a combination of ¹H NMR integra-

tion and isolated yield. An analytical sample of the 15/1

mixture of nitronates 9b and 9a could not be obtained since

formation of the nitroso acetal occurred during the removal of

residual solvent from the sample. Nitronate 9a was found to

be identical by ¹H NMR to the nitronate obtained from the

SnCl₄-promoted [4 + 2] cycloaddition. Data for 9b: ¹H NMR

(499.7 MHz, C₆D₆) δ 7.10-7.03 (m, 2 H), 7.02-6.92 (m, 6 H),

6.62-6.60 (m, 2 H), 5.51 (d, J ) 1.6, 0.06 H), 4.93-4.85 (m, 1

H), 4.76-4.72 (m, 2 H), 4.57 (d, J ) 2.2, 0.94 H), 3.94 (d, J )

7.1, 0.94 H), 3.76 (td, J ) 10.8, 4.6, 1 H), 3.63 (d, J ) 6.8, 0.06

H), 2.63-2.60 (m, 1 H), 2.50-2.45 (m, 1 H), 1.80 (s, 3 H), 1.78-

1.71 (m, 1 H), 1.67-1.59 (m, 3 H) 1.55-1.44 (m, 2 H), 1.38-

1.21 (m, 3 H), 1.07-1.00 (m, 1 H); ¹³C NMR (125.7 MHz, C₆D₆)

δ 144.39, 137.55, 135.50, 129.46, 128.72, 128.56, 128.29,

127.24, 126.59, 119.10, 117.19, 104.07, 82.81, 52.09, 45.03,

39.05, 34.68, 33.18, 32.26, 25.97, 25.25, 18.15; MS (FAB) 406

(M⁺+ 1,100); TLC R_f0.33 (hexane/EtOAc, 2/1).

rotation of the two amino diols are opposite. Data for (-)-

11a : ¹H NMR (499.7 MHz, CD₃OD) δ 7.32-7.29 (m, 2 H),

7.24-7.21 (m, 3 H), 3.75 (dd, J ) 10.8, 7.1, 1 H), 3.66 (dd, J )

10.8, 5.7, 1 H), 3.52 (dd, J ) 10.3, 3.7, 1 H), 3.34 (dd, J ) 10.5,

3.7, 1 H), 2.70 (d, J ) 10.7, 1 H), 2.50 (ddddd, J ) 10.7, 9.2,

7.9, 6.7, 3.7, 1 H), 2.16 (dt, J ) 12.8, 7.9, 1 H), 2.01 (tdd, J )

8.5, 7.1, 5.6, 1 H), 1.48 (dt, J ) 12.8, 9.2, 1 H), 0.84 (s, 3 H);

¹³C NMR (125.7 MHz, CD₃OD) δ 141.25, 130.28, 129.24,

127.70, 65.34, 64.22, 62.66, 60.72, 51.15, 44.98, 31.24, 27.55;

MS (FAB) 236 (M⁺+ 1, 100); TLC R_f0.49 (CHCl₃/CH₃OH/

NH₄OH, 10/5/1); optical rotation [R]²⁵_D) -39.7° (c ) 0.25, CH₃-

OH).

Gen er a l P r oced u r e for Acyla tion of Am in o Diols

(Gen er a l P r oced u r e V). The preparation of (+)-12a from

(-)-11a will serve to illustrate the general procedure utilized.

[(1R,3S,4R,5R)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-

cyclop en ta n ed im eth a n ol Dia ceta te ((+)-12a ). The amino

diol (-)-11a (18 mg, 0.077 mmol) was dissolved in pyridine (1

mL) and acetic anhydride (1 mL) and was left to stir at room

temperature for 1.5 h. The light yellow reaction mixture was

concentrated in vacuo to afford a yellow oil. The crude organic

concentrate was purified by silica gel column chromatography

(EtOAc/hexane, 1/1) to provide 23 mg (83%) of triacetate (+)-

12a as clear oil. The enantiomeric excess was determined to

be >99% by chiral HPLC. Data for (+)-12a : ¹H NMR (499.7

MHz, CDCl₃) δ 7.35-7.32 (m, 2 H), 7.28-7.25 (m, 1 H), 7.17-

7.15 (m, 2 H, 5.39 (s, 1 H), 4.16 (ABX, J _ab) 11.0, J _ax) 5.6, 1

Gen er a l P r oced u r e for [3 + 2] Cycloa d d ition s of Nitr o-

n a tes (Gen er a l P r oced u r e III). The preparation of 10a

from 9a will serve to illustrate the general procedure utilized.

(1S,6R,7R,8R,9R )-9-Met h yl-8-p h en yl-6-[(1R,2S)-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (10a ). A solution of nitronate 9a (397 mg, 0.98 mmol)

in benzene (10 mL) was added to a suspension of sodium

bicarbonate (576 mg, 6.86 mmol, 7 equiv) in benzene (90 mL),

and the mixture was heated to reflux for 10 h. After cooling

to room temperature, the mixture was concentrated and the

sodium bicarbonate was removed by filtration through a cotton

pipet plug, washing with TBME (25 mL). Purification of the

residue by column chromatography using basic alumina (III)

(hexane/TBME, 6/1) afforded the nitroso acetal 10a as a white

foam. An analytical sample of 10a as a clear glass (396 mg,

100%) was obtained by heating the foam in vacuo for 7 days

at 70 °C: ¹H NMR (400 MHz, C₆D₆) δ 7.48-7.46 (m, 2 H),

7.37-7.33 (m, 2 H), 7.17-7.11 (m, 3 H), 7.07-7.03 (m, 1 H),

6.83-6.81 (m, 2 H) 4.97 (d, J ) 2.7, 1 H), 4.53-4.47 (m, 1 H),

4.25-4.23 (m, 1 H), 4.10-4.06 (m, 1 H), 3.40 (s, 1 H), 2.68-

2.61 (m, 1 H), 2.20-2.18 (m, 1 H), 2.04-1.99 (m, 2 H), 1.92-

1.90 (m, 1 H) 1.82-1.78 (m, 1 H), 1.63-1.60 (m, 1 H)), 1.51-

1.48 (m, 1 H), 1.44-1.35 (m, 1 H), 1.25-1.11 (m, 4 H) 0.89 (s,

3 H); ¹³C NMR (100.6 MHz, C₆D₆) δ 145.43, 141.17, 129.11,

128.80, 128.56, 128.46, 126.70, 126.05, 99.86, 88.29, 79.82,

73.63, 51.66, 46.93, 45.78, 44.42, 35.98, 35.32, 30.70, 26.59,

24.82, 19.74; IR (CHCl₃) 3010, 2937, 1076; MS (FAB) 406 (M⁺

+ 1, 51), 159 (100); TLC R_f0.50 (hexane/EtOAc, 2/1); optical

H), 4.16 (ABX, J _bx) 7.4, 1 H), 4.08 (ABX, J _ab) 10.2, J _ax

)

3.5, 1 H), 3.92 (ABX, J _bx) 6.3, 1 H), 3.43 (d, J ) 11.2, 1 H),

2.73-2.65 (m, 1 H), 2.58-2.53 (m, 1 H), 2.23-2.17 (m, 1 H),

2.08 (s, 3 H), 1.93 (s, 3 H), 1.83 (s, 3 H), 1.70-1.64 (m, 1 H),

1.07 (s, 3 H); TLC R_f0.31 (EtOAc/hexane, 2/1); optical rotation

[R]²³) 41.5° (c ) 1.06, CHCl₃); chiral HPLC ((R,R)-Whelk-

D

O1, (i-PrOH/hexanes, 55/45), 0.5 mL/min); t_R(+)-12a 17.32 min

(>99%), >99% ee.

(1R ,6S ,7S,8S,9S )-9-Met h yl-8-p h en yl-6-[(1R ,2S )-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (10b). According to general procedure III, a 15/1 (9b/

9a ) mixture of nitronate 9b (506 mg, 1.37 mmol) was added

to a suspension of sodium bicarbonate (806 mg, 9.6 mmol, 7

equiv) in benzene (137 mL) and the mixture was heated to

reflux for 18 h. Purification by column chromotography basic

alumina (III) (hexane/TBME, 6/1) afforded the nitroso acetal

10b as a 25/1 (10b/10a ) mixture. Nitroso acetal 10b was

obtained analytically pure as a white solid (536 mg, 96% yield)

by heating the foam in vacuo for 6 days at 80 °C: ¹H NMR

(499.7 MHz, C₆D₆) δ 7.11-7.02 (m, 8 H), 6.98-6.96 (m, 2 H)

4.98 (d, J ) 2.9, 0.05 H), 4.27 (d, J ) 2.2, 0.95 H), 4.12 (s, 1

H), 4.08 (dd, J ) 7.7, 2.7, 1 H), 4.01 (dd, J ) 7.7, 7.7, 1 H),

3.74 (td, J ) 10.4, 4.4, 1 H), 2.73-2.70 (m, 1 H), 2.56-2.51

(m, 1 H), 2.01-1.96 (m, 1 H), 1.90-1.83 (m, 2 H) 1.71-1.62

(m, 3 H), 1.50-1.48 (m, 1 H), 1.42-1.34 (m, 1 H), 1.28-1.20

(m, 1 H), 1.34-1.05 (m, 1 H) 1.01 (s, 3 H), 0.97-0.92 (m, 1 H);

¹³C NMR (125.6 MHz, C₆D₆) δ 145.07, 140.82, 129.08, 128.69,

128.34, 128.78, 126.76, 126.31, 106.81, 87.39, 81.60, 79.38,

51.85, 47.76, 45.87, 44.83, 35.81, 35.16, 33.20, 26.18, 25.43,

19.97; IR (CHCl₃) 3025, 3021, 3012, 2936; MS (FAB) 406

(M⁺+1, 44), 159 (100); TLC R_f0.48 (hexane/EtOAc, 2/1); optical

rotation [R]²³) -220.0° (c ) 1.0, CHCl₃). Anal. Calcd for

D

C

₂₆H₃₁NO₃(405.534): C, 77.01; H, 7.71; N, 3.45. Found: C,

76.90; H, 7.81; N, 3.41.

Gen er a l P r oced u r e for Nick el Bor id e Red u ction of

Nitr oso Aceta ls (Gen er a l P r oced u r e IV). The preparation

of (-)-11a from 10a will serve to illustrate the general

procedure utilized.

[(1R,3S,4R,5R)-4-Am in o-4-m eth yl-5-p h en yl]-1,3-cyclo-

p en ta n ed im eth a n ol ((-)-11a ). Nickel chloride (87 mg, 0.678

mmol, 1.1 equiv) was added to a solution of nitroso acetal 10a

(250 mg, 0.616 mmol) in ethanol (12 mL) at room temperature

(reaction does not need to be run under N₂). Sodium borohy-

dride (70 mg, 1.83 mmol, 3 equiv) was added to the suspension,

and a black precipitate formed rapidly with concomitant

hydrogen evolution. After 15 min, another 3 equiv of NaBH₄

(70 mg) was added. After 40 min, the ethanol was removed

in vacuo to provide a black solid. The crude organic concen-

trate was purified by silica gel column chromatography (CHCl₃/

MeOH, 10/1 (100 mL), then CHCl₃/MeOH/NH₄OH, 10/5/1) to

afford 119 mg (82% yield) of amino diol (-)-11a as a light

brown solid and 100 mg (94% yield) of recovered (-)-(1R,2S)-

phenylcyclohexanol ((-)-4). Recrystallization (acetonitrile) of

the amino diol afford a white microcrystalline material. The

¹H NMR, ¹³C NMR, and MS of amino diol (-)-11a were

identical to the data obtained for amino diol (+)-11a which is

derived from a tandem sequence using MAPh as the Lewis

acid in the [4 + 2] cycloaddition. However, the signs of the

rotation [R]²³) -11.0° (c ) 1.1, CHCl₃). Anal. Calcd for

D

C

₂₆H₃₁NO₃(405.534): C, 77.01; H, 7.71; N, 3.45. Found: C,

77.24; H, 7.65; N, 3.54.

(1S,3R,4S,5S)-4-Am in o-4-m et h yl-5-p h en yl]-1,3-cyclo-

p en ta n ed im eth a n ol ((+)-11a ). According to general proce-

dure IV, nickel chloride (155 mg, 1.10 mmol, 1.1 equiv) was

added to a solution of nitroso acetal 10b (405 mg, 1.0 mmol)

in ethanol (20 mL). NaBH₄(125 mg, 3.3 mmol, 3 equiv) was

added to the suspension, and after 15 min, additional NaBH₄

(125 mg, 3.3 mmol, 3 equiv) was added. After 30 min, the

ethanol was removed in vacuo providing a black solid. The

crude organic concentrate was purified by silica gel column

chromatography (CHCl₃/MeOH, 10/1 (100 mL), then CHCl₃/

MeOH/NH₄OH, 10/5/1) to afford 169 mg (72% yield) of amino

diol (+)-11a as a light brown solid and 162 mg (94% yield) of

recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-4). An analyti-

cal sample of (+)-11a was obtained by recrystallization (aceto-

6190 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

nitrile) to provide a white microcrystalline material. The

analytical data for (+)-11a , except for the sign of the rotation,

was identical to the data obtained for amino diol (-)-11a which

was derived from a tandem sequence using SnCl₄as the Lewis

acid in the [4 + 2] cycloaddition. Data for (+)-11a : mp 189-

(4R ,5S ,6S)-4-Cycloh exyl-3-m et h yl-5-(2-p r op en yl)-6-

[(1R,2S)-(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H-[1,2]-

oxa zin e 2-Oxid e (14b). According to general procedure II,

a solution of MAPh (2.0 mmol, 2.0 equiv) in CH₂Cl₂(10 mL)

was transferred, via cannula, to a second reaction vessel

containing a -60 °C solution of nitroalkene 13 (169 mg, 1.0

mmol) and vinyl ether (-)-6 (364 mg, 1.5 mmol, 1.5 equiv) in

CH₂Cl₂(5 mL). The resulting dark brown solution was allowed

to warm slowly to -5 °C over a 3 h period and was then left

to stir at -5-0 °C for 66 h (the color faded to a light brown),

after which time the reaction was quenched with H₂O (6 mL).

After an aqueous extractive workup, the crude material was

purified by silica gel column chromatography (hexane/EtOAc,

8/1 (900 mL), 7/1 (800 mL), 6/1) to afford 353 mg of ap-

proximately 7/1 (14b/14a ) mixture of 14b and 14a and 16 mg

of 14d . The exo/endo selectivity for the reaction was deter-

mined to be approxiamately 22/1 ((14b + 14a )/14d ). An

analytical sample of the 7/1 mixture of nitronates 14b and 14a

could not be obtained since formation of the nitroso acetal 15b

occurred during the removal of residual solvent from the

sample. Data for 14b: ¹H NMR (499.7 MHz, C₆D₆) δ 7.18-

7.03 (m, 5 H), 5.52-5.45 (m, 0.11 H), 5.32-5.24 (m, 0.89 H),

4.90-4.87 (m, 2 H), 4.52 (d, J ) 5.5, 1 H), 3.68 (td, J ) 10.4,

4.2, 1 H), 3.04-3.02 (m, 1 H), 2.51-2.46 (m, 1 H), 1.92-0.73

(m, 25 H); TLC R_f0.20 (hexane/EtOAc, 3/1).

1

191 °C (CH₃CN); H NMR (499.7 MHz, CD₃OD) δ 7.32-7.30

(m, 2 H), 7.24-7.20 (m, 3 H), 3.75 (dd, J ) 10.8, 7.1, 1 H),

3.65 (dd, J ) 10.8, 5.7, 1 H), 3.52 (dd, J ) 10.3, 3.7, 1 H), 3.34

(dd, J ) 10.5, 3.7, 1 H), 2.70 (d, J ) 10.7, 1 H), 2.49 (ddddd, J

) 10.7, 9.2, 7.9, 6.7, 3.7, 1 H), 2.16 (dt, J ) 12.8, 7.9, 1 H),

2.01 (tdd, J ) 8.5, 7.1, 5.6, 1 H), 1.48 (dt, J ) 12.8, 9.2, 1 H),

0.83 (s, 3 H); ¹³C NMR (125.7 MHz, CD₃OD) δ 140.33, 129.26,

128.21, 126.65, 64.61, 63.31, 61.50, 59.85, 50.21, 43.96, 30.33,

26.75; IR (KBr) 3318, 3271, 3264, 3257, 2956, 2922, 2898, 1040,

1036, 1013; MS (FAB) 236 (M⁺+ 1, 100); TLC R_f0.49 (CHCl₃/

CH₃OH/NH₄OH, 10/5/1); optical rotation [R]²⁵) 31.9° (c )

D

0.75, CH₃OH). Anal. Calcd for C₁₄H₂₁NO₂(235.33): C, 71.46;

H, 8.99; N, 5.95. Found: C, 71.48; H, 9.10; N, 5.97.

[(1S,3R,4S,5S)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-

cyclop en ta n ed im eth a n ol Dia ceta te ((-)-12a ). According

to general procedure V, the amino diol (+)-11a (25 mg, 0.106

mmol) was dissolved in pyridine (1.5 mL) and acetic anhydride

(1.5 mL) and was left to stir at room temperature for 1.5 h.

Purification by silica gel column chromatography (Et₂O) to

provide 29 mg (77%) of triacetate (-)-12a as clear oil. The

enantiomeric excess was determined to be 95% by chiral

HPLC. Data for (-)-12a : ¹H NMR (499.7 MHz, CDCl₃) δ

7.35-7.32 (m, 2 H), 7.28-7.25 (m, 1 H), 7.17-7.15 (m, 2 H),

5.39 (s, 1 H), 4.16 (ABX, J _ab) 11.0, J _ax) 5.6, 1 H), 4.16 (ABX,

J _bx) 7.4, 1 H), 4.08 (ABX, J _ab) 10.2, J _ax) 3.5, 1 H), 3.92

(ABX, J _bx) 6.3, 1 H), 3.43 (d, J ) 11.2, 1 H), 2.73-2.65 (m, 1

H), 2.58-2.53 (m, 1 H), 2.23-2.17 (m, 1 H), 2.08 (s, 3 H), 1.93

(s, 3 H), 1.83 (s, 3 H), 1.70-1.64 (m, 1 H), 1.07 (s, 3 H); TLC

(1S,6R,7R,8S,9R)-8-Cycloh exyl-9-m eth yl-6-[(1R,2S)-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (15a ). According to general procedure III, a 6.9/1

mixture of nitronates 14a and 14b (288 mg, 0.554 mmol) was

added to a suspension of sodium bicarbonate (47 mg, 0.554

mmol, 1 equiv) in benzene (56 mL) and the mixture was heated

to reflux for 15 min. Purification by column chromatography

on basic alumina (III) (hexane/TBME, 10/1) afforded 201 mg

(88% yield) of analytically pure nitroso acetal 15a (determined

R_f0.31 (EtOAc/hexane, 2/1); optical rotation [R]²³) -40.3°

D

1

(c ) 1.45, CHCl₃); chiral HPLC ((R,R)-Whelk-O1, (i-PrOH/

hexanes, 55/45), 0.5 mL/min) t_R(-)-12a 14.58 min (96.3%), t_R

(+)-12a 17.98 min (3.7%), 93% ee.

to be a 20/1 (15a /15b) mixture by H NMR integration) as a

clear glass: ¹H NMR (499.7 MHz, C₆D₆) δ 7.42-7.40 (m, 2 H),

7.32-7.28 (m, 2 H), 7.14-7.11 (m, 1 H), 4.98 (d, J ) 2.3, 1 H),

4.40 (td, J ) 10.5, 4.2, 1 H), 4.17 (dd, J ) 7.7, 2.7, 1 H), 4.09

(dd, J ) 7.9, 7.7, 1 H), 2.60 (ddd, J ) 12.4, 10.8, 3.7, 1H), 2.23-

2.19 (m, 1 H), 1.92 (d, J ) 4.9, 1 H), 1.86-1.81 (m, 1 H), 1.80-

1.76 (m, 2 H), 1.65-1.54 (m, 5 H) 1.49-1.46 (m, 1 H), 1.41-0.94

(m, 14 H), 0.86-0.77 (m, 1 H), 0.66-0.58 (m, 1 H); ¹³C NMR

(125.6 MHz, C₆D₆) δ 145.30, 128.74, 128.25, 125.82, 100.30,

88.06, 79.57, 73.61, 51.45, 44.86, 44.08, 40.55, 37.02, 36.45,

35.29, 33.32, 30.77, 29.60, 26.97, 26.83, 26.69, 26.56, 24.83,

18.94; IR (CHCl₃) 2933; MS (FAB) 412 (M⁺+ 1, 88), 159 (100);

(4S,5R,6R)-4-Cycloh exyl-3-m et h yl-5-(2-p r op en yl)-6-

[(1R,2S)-(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H-[1,2]-

oxa zin e 2-Oxid e (14a ) a n d (4S,5R,6S)-4-Cycloh exyl-3-

m et h yl-5-(2-p r op en yl)-6-[(1R,2S)-(2-p h en ylcycloh exyl)-

oxy]-5,6-d ih yd r o-4H-[1,2]-oxa zin e 2-Oxid e (14c). Accord-

ing to general procedure I, tin tetrachloride (0.117 mL, 1.0

mmol, 1 equiv) was added to a -78 °C solution of nitroalkene

13 (169 mg, 1.0 mmol) in CH₂Cl₂(10 mL) and the resulting

colorless complex was left to stir for 15 min. A solution of vinyl

ether (-)-6 (485 mg, 2.0 mmol, 2.0 equiv) in CH₂Cl₂(1 mL)

was added rapidly to the cold reaction mixture via syringe,

and the reaction mixture turned slightly brown. The reaction

was left to stir at -78 °C for an additional 5 min and was

then quenched with 1 N NaOH/MeOH (4 mL). After extractive

aqueous workup (do not heat when concentrating solvent), the

crude organic concentrate was purified by silica gel column

chromatography (hexane/EtOAc, 8/1 (900 mL), 6/1 (700 mL),

2/1) to afford 229 mg of 14a as a 6.9/1 (14a /14b) mixture by

¹H NMR integration and 99 mg of nitronate diastereomers 14c.

The overall yield of the reaction was 328 mg (80%) with an

overall selectivity of 6.9/1/3.4 (14a /14b/24c). Nitronate 14b

was found to be identical by ¹H NMR to the nitronate 14b

obtained from a MAPh-promoted [4 + 2] cycloaddition. Data

for 14a : ¹H NMR (499.7 MHz, C₆D₆) δ 7.18-7.03 (m, 5 H),

5.52-5.45 (m, 0.11 H), 5.32-5.24 (m, 0.89 H), 4.90-4.87 (m,

2 H), 4.52 (d, J ) 5.5, 1 H), 3.68 (td, J ) 10.4, 4.2, 1 H), 3.04-

3.02 (m, 1 H), 2.51-2.46 (m, 1 H), 1.92-0.73 (m, 25 H); TLC

R_f20 (hexane/EtOAc, 3/1). Data for 14c: ¹H NMR (499.7 MHz,

CDCl₃)) δ 7.31-7.26 (m, 2 H), 7.23-7.19 (m, 3 H), 5.35-5.26

(m, 1 H), 4.85 (d, J ) 10.5, 1 H), 4.83 (d, J ) 3.4, 1 H), 4.72 (d,

J ) 17.0, 1 H), 3.78-3.68 (m, 1 H), 2.52-2.45 (m, 2 H), 2.04-

2.02 (m, 4 H), 1.94-1.61 (m, 10 H), 1.57-1.35 (m, 5 H), 1.33-

1.04 (m, 5 H), 0.93-0.85 (m, 1 H); ¹³C NMR (125.7 MHz,

CDCl₃)) δ 144.44, 135.84, 128.44, 127.87, 126.51, 123.96,

116.52, 106.22, 84.45, 51.75, 44.19, 38.08, 36.34, 35.92, 34.73,

34.02, 30.54, 30.05, 27.15, 27.04, 26.18, 25.68, 24.97, 21.11

(CH₃); IR (CHCl₃) 2934; MS (FAB) 412 (M⁺+ 1, 87), 159 (100);

TLC R_f0.16 (hexane/EtOAc, 3/1).

TLC R_f0.48 (hexane/EtOAc, 3/1); optical rotation [R]²⁴

)

D

-143.3° (c ) 0.98, CHCl₃). Anal. Calcd for C₂₆H₃₇NO₃(411.59):

C, 75.87; H, 9.06; N, 3.40. Found: C, 75.86; H, 9.18; N, 3.39.

(1S,6S,7R,8S,9R)-8-Cycloh exyl-9-m eth yl-6-[(1R,2S)-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (15c). According to general procedure III, nitronate

14c (99 mg, 0.240 mmol) was added to a suspension of sodium

bicarbonate (141 mg, 1.68 mmol, 7 equiv) in benzene (24 mL)

and the mixture was heated to reflux for 1.5 h. Purification

by column chromatography on basic alumina (III) (10:1 hexane/

TBME) afforded 93 mg (94% yield) of analytically pure nitroso

acetal 15c as a white crystalline solid: mp 113-115 °C

(TBME/hexane); ¹H NMR (499.7 MHz, C₆D₆) δ 7.16-7.13 (m,

2 H), 7.10-7.06 (m, 3 H), 4.50 (d, J ) 6.0, 1 H), 4.32 (dd, J )

7.0, 3.9, 1 H), 4.16 (dd, J ) 9.0, 7.1, 1 H), 3.66 (td, J ) 10.5,

4.4, 1 H), 2.68-2.65 (m, 1H), 2.49-2.43 (m, 1 H), 2.05-2.01

(m, 1 H), 1.94 (d, J ) 13.0, 1 H), 1.78 (t, J ) 5.9, 1 H), 1.70-

1.57 (m, 3 H) 1.53-1.45 (m, 6 H), 1.39-1.31 (m, 1 H), 1.27-

0.94 (m, 10 H), 0.88-0.81 (m, 1 H), 0.70-0.63 (m, 1 H), 0.51-

0.44 (m, 1 H); ¹³C NMR (125.6 MHz, C₆D₆) δ 144.92, 128.34,

128.29, 127.49, 106.46, 84.35, 82.57, 78.35, 52.06, 48.70, 48.59,

40.92, 36.07, 34.70, 34.21, 33.09, 29.73, 29.70, 26.85, 26.53,

26.48, 26.16, 25.33, 21.23; IR (CHCl₃) 2933; MS (FAB) 412 (M⁺

+ 1, 83), 159 (100); TLC R_f0.46 (hexane/EtOAc, 3/1); optical

rotation [R]²⁴) 59.90° (c ) 1.01, CHCl₃). Anal. Calcd for

D

C

₂₆H₃₇NO₃(411.59): C, 75.87; H, 9.06; N, 3.40. Found: C,

75.80; H, 9.06; N, 3.28.

[(1R,3S,4R,5S)-4-Am in o-5-cycloh exyl-4-m eth yl]-1,3-cy-

clop en ta n ed im eth a n ol ((+)-16). According to general pro-

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6191

cedure IV, nickel chloride (64 mg, 0.490 mmol, 1.2 equiv) was

added to a solution of nitroso acetal 15a (168 mg, 0.408 mmol)

in ethanol (9 mL). NaBH₄(93 mg, 2.45 mmol, 6 equiv) was

added to the suspension, and after ca. 15 min NaBH₄(93 mg,

2.45 mmol, 6 equiv) was added. After ca. 40 min, the ethanol

was removed in vacuo providing a black solid. Purification by

silica gel column chromatography (CHCl₃/MeOH, 10/1 (100

mL), then CHCl₃/MeOH/NH₄OH, 10/5/1) afforded 81 mg (82%

yield) of amino diol (+)-16 as a white foam and 63 mg (90%)

of recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-4). The ana-

lytical data for (+)-16, except for the sign of the rotation, was

identical to the data obtained for amino diol (-)-16 which was

derived from a tandem sequence using MAPh as the Lewis

acid in the [4 + 2] cycloaddition. Data for (+)-16: ¹H NMR

(499.7 MHz, CD₃OD) δ 3.72-3.64 (m, 3 H), 3.40 (dd, J ) 10.1,

5.0, 1 H), 2.23-2.17 (m, 1 H), 1.97-1.85 (m, 3 H), 1.77-1.74

(m, 2 H), 1.68-1.47 (m, 6 H), 1.38-1.11 (m, 8 H); ¹³C NMR

(125.7 MHz, CD₃OD) δ 67.46, 65.66, 61.75, 58.70, 50.24, 39.34,

38.45, 33.72, 29.46, 28.92, 27.19, 26.51, 26.47, 19.37; IR (KBr)

3318, 3271, 3264, 3257, 2956, 2922, 2898, 1040, 1036, 1013;

MS (FAB) 236 (M⁺+ 1, 100); TLC R_f0.57 (CHCl₃/CH₃OH/

1 H), 2.39-2.33 (m, 1 H), 2.26-2.18 (m, 1 H), 2.06 (s, 3 H),

2.05 (s, 3 H) 2.02-1.98 (m, 1 H), 1.92 (s, 3 H), 1.80-1.78 (m,

1 H), 1.74-1.72 (m, 2 H), 1.66-1.63 (m, 3 H), 1.59-1.53 (m, 1

H), 1.51-1.45 (m, 1 H) 1.43 (s, 3 H), 1.33-1.19 (m, 2 H), 1.15-

1.01 (m, 3 H); ¹³C NMR (125.7 MHz, CDCl₃) δ 171.17, 170.90,

169.43, 69.13, 65.05, 64.49, 54.08, 46.47, 37.88, 36.36, 33.89,

30.25, 30.05, 26.85, 26.42, 26.22, 24.48, 20.99, 20.96, 20.19;

IR (CHCl₃) 1732, 1265, 1243; MS (FAB) 368 (M⁺+ 1, 100);

TLC R_f0.36 (EtOAc/hexane, 2/1); optical rotation [R]²²_D) 23.4°

(c ) 0.83, CHCl₃). Anal. Calcd for C₂₀H₃₃NO₅(367.49): C,

65.37; H, 9.05; N, 3.81. Found: C, 65.11; H, 9.25; N, 3.61.

(1R,6S,7S,8R,9S)-8-Cycloh exyl-9-m eth yl-6-[(1R,2S)-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (15b). According to general procedure III, a 7:1

mixture of nitronates 14b and 14a (353 mg, 0.858 mmol) was

added to a suspension of sodium bicarbonate (216 mg, 2.57

mmol, 3 equiv) in benzene (85 mL) and the mixture was heated

to reflux for 2 h. Purification by column chromatography on

basic (III) alumina (hexane/Et₂O, 7/1) afforded 280 mg of

analytically pure nitroso acetal 15b (determined to be a >25:1

1

(15b/15a ) mixture by H NMR integration) as a clear viscous

NH₄OH, 10/5/1); optical rotation [R]²²) 27.1° (c ) 1.0, CH₃-

oil along with 43 mg of nitroso acetal 15a as a clear glass for

a combined yield of 91%: ¹H NMR (499.7 MHz, C₆D₆) δ 7.20-

7.15 (m, 3 H), 7.09-7.06 (m, 2 H) 4.97 (d, J ) 2.7, 0.05 H),

4.27 (d, J ) 2.9, 0.95 H), 4.03-3.98 (m, 2 H). 3.67 (td, J )

10.5, 4.4, 1 H), 2.67-2.64 (m, 1 H), 2.57 (d, J ) 5.4, 1 H), 2.53-

2.48 (m, 1 H), 1.83-1.70 (m, 1 H), 1.70-1.53 (m, 8 H) 1.5-

1.43 (m, 2 H), 1.36 (dq, J ) 12.9, 3.4, 1 H), 1.26-0.92 (m, 11

H), 0.85-0.82 (m, 1 H), 0.67 (dq, J ) 11.9, 3.2, 1 H); ¹³C NMR

(125.6 MHz, C₆D₆) δ 145.33, 128.39, 128.24, 126.26, 107.47,

87.10, 81.79, 79.18, 51.94, 45.50, 45.21, 40.84, 37.03, 36.26,

35.20, 33.72, 33.41, 29.97, 26.97, 26.85, 26.66, 26.21, 25.41,

19.43; IR (CHCl₃) 2932; MS (FAB) 412 (M⁺+ 1, 65), 159 (100);

TLC R_f0.48 (hexane/EtOAc, 3/1); optical rotation [R]²³_D) 1.0°

(c ) 1.0, CHCl₃). Anal. Calcd for C₂₆H₃₇NO₃(411.59): C,

75.87; H, 9.06; N, 3.40. Found: C, 75.96; H, 9.28; N, 3.12.

[(1S,3R,4S,5R)-4-Am in o-5-cycloh exyl-4-m eth yl]-1,3-cy-

clop en ta n ed im eth a n ol ((-)-16). According to general pro-

cedure IV, nickel chloride (93 mg, 0.714 mmol, 1.2 equiv) was

added to a solution of nitroso acetal 15b (245 mg, 0.595 mmol)

in ethanol (11 mL). NaBH₄(68 mg, 1.79 mmol, 3 equiv) was

added to the suspension, and after 15 min, NaBH₄(68 mg,

1.79 mmol, 3 equiv) was added. After 40 min, the ethanol was

removed in vacuo providing a black solid. Purification by silica

gel column chromatography (CHCl₃/MeOH, 10/1 (100 mL),

then CHCl₃/MeOH/NH₄OH, 10/5/1) afforded 138 mg (96%

yield) of amino diol (-)-16 as a white foam and 0.101 g (98%)

of recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-4). The ana-

lytical data for (-)-16, except for the sign of the rotation, were

identical to the data obtained for amino diol (+)-16 which was

derived from a tandem sequence using SnCl₄as the Lewis acid

D

OH); HRMS (FAB) Calcd for C₁₄H₂₈NO₂, 242.21200; Found,

242.21210.

[(1R,3S,4R,5S)-4-Acetyla m in o-5-cycloh exyl-4-m eth yl]-

1,3-cyclop en ta n ed im eth a n ol Dia ceta te ((+)-17). Accord-

ing to general procedure V, amino diol (+)-16 (71 mg, 0.294

mmol) was dissolved in pyridine (4 mL) and acetic anhydride

(4 mL) and was left to stir at room temperature for 1.5 h.

Purification by silica gel column chromatography (Et₂O)

provided 87 mg (80%) of analytically pure triacetate (+)-17

as a clear oil. The enantiomeric excess was determined to be

95% by chiral HPLC. The analytical data for (+)-17, except

for the sign of the rotation, were identical to the data obtained

for triacetate (-)-17 which was derived from

a tandem

sequence using MAPh as the Lewis acid in the [4 + 2]

cycloaddition. Data for (-)-17: ¹H NMR (499.7 MHz, CDCl₃)

δ 5.63 (s, 1 H), 4.13 (dd, J ) 10.1, 4.8, 1 H), 4.10 (dd, J ) 11.3,

4.1, 1 H), 4.03 (dd, J ) 11.3, 6.8, 1 H), 3.85 (dd, J ) 10.6, 8.6,

1 H), 2.39-2.34 (m, 1 H), 2.26-2.18 (m, 1 H), 2.07 (s, 3 H)

2.05 (s, 3 H), 2.04-1.98 (m, 1 H), 1.92 (s, 3 H), 1.79 (dd, J )

7,7, 4.2, 1 H), 1.75-1.72 (m, 2 H), 1.66-1.64 (m, 3 H), 1.60-

1.54 (m, 1 H), 1.51-1.46 (m, 1 H) 1.43 (s, 3 H), 1.34-1.20 (m,

2 H), 1.16-1.01 (m, 3 H); ¹³C NMR (125.7 MHz, CDCl₃) δ

171.17, 170.90, 169.43, 69.13, 65.05, 64.48, 54.07, 46.47, 37.88,

36.36, 33.89, 30.25, 30.05, 26.86, 26.42, 26.23, 24.49, 20.99,

20.96, 20.20; TLC R_f0.36 (EtOAc/hexane, 2/1); optical rotation

[R]²³) 25.3° (c ) 0.80, CHCl₃); chiral HPLC (Chiralcel OJ ,

D

(hexane/i-PrOH, 95/5), 0.4 mL/min); t_R(-)-17 42.19 min (2.2%),

t_R(+)-17 63.40 min (97.8%), 95% ee.

[(1R,3S,4R,5S)-4-Acetyla m in o-5-cycloh exyl-4-m eth yl]-

1,3-cyclop en ta n ed im eth a n ol Dia ceta te ((+)-17). Accord-

ing to general procedure IV, nickel chloride (20 mg, 0.155

mmol, 1.2 equiv) was added to a solution of nitroso acetal 15c

(53 mg, 0.129 mmol) in ethanol (4 mL). NaBH₄(29 mg, 1.54

mmol, 6 equiv) was added to the suspension, and after 15 min,

NaBH₄(29 mg, 1.54 mmol, 6 equiv) was added. After 1 h, the

ethanol was removed in vacuo providing a black solid. Puri-

fication by silica gel column chromatography (CHCl₃/MeOH,

10/1 (100 mL) then CHCl₃/MeOH/NH₄OH, 10/5/1) afforded 17

mg (53% yield) of amino diol (+)-16 as a white foam and 16

mg (72%) of recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-

4).

According to general procedure V, amino diol (+)-16 (17 mg,

0.069 mmol) was dissolved in pyridine (2.0 mL) and acetic

anhydride (2.0 mL) and was left to stir at room temperature

for 2.0 h. Purification by silica gel column chromatography

(Et₂O) provided 20 mg (79%) of analytically pure triacetate

(+)-17 as a clear oil. The analytical data for (+)-17, except

for the sign of the rotation, were identical to the data obtained

1

in the [4 + 2] cycloaddition. Data for (-)-16: H NMR (499.7

MHz, CD₃OD) δ 3.85 (dd, J ) 11.5, 3.5, 1 H), 3.73 (dd, J )

11.6, 3.9, 1 H), 3.66 (dd, J ) 9.9, 2.4, 1 H), 3.46 (dd, J ) 9.9,

3.1, 1 H), 2.38-2.37 (m, 1 H), 2.03-1.93 (m, 2 H), 1.88-1.65

(m, 6 H), 1.58-1.46 (m, 5 H), 1.42-1.11 (m, 5 H); ¹³C NMR

(125.7 MHz, CD₃OD) δ 65.90, 64.14, 59.52, 56.96, 48.36, 38.34,

38.12, 32.74, 28.23, 27.29, 26.92, 26.26, 26.17, 18.37; TLC R_f

0.57 (CHCl₃/CH₃OH/NH₄OH, 10/5/1); optical rotation [R]²⁵

-31.2° (c ) 0.96, CH₃OH).

)

D

[(1S,3R,4S,5R)-4-Acetyla m in o-5-cycloh exyl-4-m eth yl]-

1,3-cyclop en ta n ed im eth a n ol Dia ceta te ((-)-17). Accord-

ing to general procedure V, amino diol (-)-16 (25 mg, 0.106

mmol) was dissolved in pyridine (1.5 mL) and acetic anhydride

(1.5 mL) and was left to stir at room temperature for 1.5 h.

Purification by silica gel column chromatography (Et₂O)

provided 29 mg (77%) of analytically pure triacetate (-)-17

as a clear oil. The enantiomeric excess was determined to be

95% by chiral HPLC. The analytical data for (-)-17, except

for the sign of the rotation, were identical to the data obtained

for triacetate (-)-17 which was derived from

a

tandem

for triacetate (+)-17 which was derived from a tandem

sequence using MAPh as the Lewis acid in the [4 + 2]

sequence using SnCl₄as the Lewis acid in the [4 + 2]

1

cycloaddition. Data for (+)-17: H NMR (499.7 MHz, CDCl₃)

cycloaddition. Data for (-)-17: H NMR (499.7 MHz, CDCl₃)

δ 5.64 (s, 1 H), 4.13 (dd, J ) 10.1, 4.8, 1 H), 4.10 (dd, J ) 11.3,

4.1, 1 H), 4.03 (dd, J ) 11.3, 6.8, 1 H), 3.85 (dd, J ) 10.6, 8.6,

δ 5.64 (s, 1 H), 4.13 (dd, J ) 10.1, 4.8, 1 H), 4.10 (dd, J ) 11.3,

4.1, 1 H), 4.03 (dd, J ) 11.3, 6.8, 1 H), 3.85 (dd, J ) 10.6, 8.6,

6192 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

1 H), 2.39-2.34 (m, 1 H), 2.25-2.19 (m, 1 H), 2.07 (s, 3 H),

2.05-2.00 (m, 4 H), 1.93 (s, 3 H), 1.81-1.78 (m, 1 H), 1.75-

1.73 (m, 2 H), 1.66-1.54 (m, 4 H), 1.51-1.44 (m, 4 H), 1.34-

1.20 (m, 2 H), 1.16-1.02 (m, 3 H); ¹³C NMR (125.7 MHz,

CDCl₃) δ 171.18, 170.90, 169.43, 69.14, 65.06, 64.49, 54.08,

46.47, 37.89, 36.36, 33.90, 30.25, 30.05, 26.86, 26.43, 26.23,

24.49, 21.00, 20.96, 20.20; TLC R_f0.36 (EtOAc/hexane, 2/1);

acetic anhydride (3 mL) and left to stir at room temperature

for 1.5 h. Purification by silica gel column chromatography

(EtOAc/hexanes, 2/1) provided 54 mg of analytically pure

triacetate 26 as a 9.5/1 (26a /26b) mixture of epimers and 35

mg of a 1.4:1 (26a /26b) mixture of epimers for a combined yield

of 59%. Data for 26b: ¹H NMR (499.7 MHz, CD₃OD) δ 7.36-

7.22 (m, 5 H), 3.76-3.69 (m, 1 H), 3.63-3.56 (m, 2 H), 3.49

(dd, J ) 10.8, 3.5, 1 H), 3.38-3.10 (m, 1 H), 2.69-2.63 (m, 1

H), 2.51-2.46 (m, 1 H), 2.24-2.10 (m, 2 H), 1.55-1.49 (m, 0.74

H), 1.36-1.30 (m, 0.26 H). Data for (-)-26a : ¹H NMR (499.7

MHz, CDCl₃) δ 7.32-7.29 (m, 2 H), 7.25-7.22 (m, 1 H), 7.18-

7.16 (m, 2 H), 5.47 (d, J ) 8.1, 0.90 H), 4.88 (d, J ) 9.0 0.10

H), 4.58 (dt, J ) 11.0, 8.5, 0.90 H), 4.38 (q, J ) 9.2, 0.10 H),

4.16 (dd, J ) 11.2, 5.6, 1 H), 4.06-4.02 (m, 2 H), 3.91 (dd, J )

11.0, 6.1, 1 H), 2.83-2.76 (m, 1 H), 2.61 (t, J ) 11.0, 1 H),

2.38-2.30 (m, 1 H), 2.28-2.22 (m, 1 H), 2.11 (s, 3 H), 1.88 (s,

3 H), 1.85 (s, 3 H), 1.43 (ddd, J ) 13.4, 9.5, 6.6, 1 H); ¹³C NMR

(125.7 MHz, CDCl₃) δ 171.17, 171.00, 170.06, 139.59, 128.85),

127.58, 127.31, 65.85, 64.79, 57.69, 53.69, 43.11, 37.38, 30.21,

23.11, 21.09, 20.63; IR (CHCl₃) 1736, 1246; MS (FAB) 348 (M⁺

+ 1, 100); TLC R_f0.22 (EtOAc/hexane, 2/1); optical rotation

optical rotation [R]²²) -23.7° (c ) 0.9, CHCl₃); chiral HPLC

D

(Chiralcel OJ , (hexane/i-PrOH, 95/5), 0.4 mL/min); t_R(-)-17

42.19 min (97.6%); t_R(+)-17 63.40 min (2.4%), 95% ee. Anal.

Calcd for C₂₀H₃₃NO₅(367.49): C, 65.37; H, 9.05; N, 3.81.

Found: C, 65.68; H, 9.27; N, 3.86.

(4 S ,5 S ,6 S )-4-P h en yl-5-(2-p r op en yl)-6-[(1 R ,2 S )-(2-

ph en ylcycloh exyl)oxy]-5,6-dih ydr o-4H-[1,2]-oxazin e 2-Ox-

id e (20a ). According to general procedure II, a solution of

MAPh (2.4 mmol, 2.0 equiv) was transferred, via cannula, to

a second reaction vessel containing a -78 °C solution of

nitroalkene 18 (179 mg, 1.2 mmol) and vinyl ether (-)-6 (436

mg, 1.8 mmol, 1.5 equiv) in CH₂Cl₂(3 mL). The resulting dark

brown solution was allowed to warm slowly to -50 °C over 1

h and then was left to stir at -50 °C for 2 h (the color faded

to a light brown), after which time the reaction was quenched

with H₂O (6 mL). After an aqueous extraction, the crude

material was purified by silica gel column chromatography

(hexane/EtOAc, 7/1 (800 mL), 6/1) to afford 432 mg (92% yield)

of a mixture of nitronates 20a and 20b and nitroso acetal 22.

[R]²¹) -28.7° (c ) 0.6, CHCl₃); chiral HPLC (Chiralcel OJ ,

D

(hexane/EtOH, 78/22), 0.7 mL/min.); t_R(-)-26a 6.32 min

(97.3%), t_R(+)-26a 8.71 min (2.7%), 94.6% ee. Anal. Calcd

for C₁₉H₂₅NO₅(347.42): C, 65.69; H, 7.25; N, 4.03. Found:

C, 65.46; H, 7.25; N, 3.98.

1

Data for 20a : H NMR (499.7 MHz, C₆D₆) δ 7.11-6.99 (m, 6

(4R,5R,6S)-4-Ben zoyloxy-5-(2-p r op en yl)-6-[(1R,2S)-(2-

ph en ylcycloh exyl)oxy]-5,6-dih ydr o-4H-[1,2]-oxazin e 2-Ox-

id e (21). According to general procedure II, a solution of

MAPh (2.6 mmol, 2.0 equiv) was transferred, via cannula, to

a second reaction vessel containing a -78 °C solution of

nitroalkene 19 (250 mg, 1.3 mmol) and vinyl ether (-)-6 (469

mg, 1.9 mmol, 1.5 equiv) in toluene (6 mL). The resulting dark

brown solution was left to stir at -78 °C for 2 h (the color

faded to a light brown), after which time the reaction was

quenched with H₂O (8 mL). After an aqueous extraction, the

crude material was purified by silica gel column chromatog-

raphy (hexane/EtOAc, 9/1 (1000 mL), 8/1) to afford 384 mg

(68% yield) of a mixture of nitronates 21 and nitroso acetal

23. Diasteremomeric ratios for the nitronates could not be

determined for this reaction. Data for 21: ¹H NMR (499.7

MHz, C₆D₆) δ 7.96-7.91 (m, 2 H), 7.14-6.88 (m, 2 H), 6.09 (d,

J ) 3.8, 1 H),5.47-5.45 (m, 1 H), 5.17-5.09 (m, 1 H), 4.76-

4.69 (m, 2 H), 4.60 (d, J ) 4.8, 1 H), 3.57 (td, J ) 11.8, 4.6, 1

H), 2.46-2.44 (m, 1 H) 2.39-2.33 (m, 1 H), 1.83-1.75 (m, 2

H), 1.70-1.57 (m, 2 H), 1.48-1.41 (m, 2 H), 1.27-0.94 (m, 3

H); TLC R_f0.29 (hexane/EtOAc, 3/1).

[(1R,3R,4R,5R)-4-Am in o-5-b en zoyloxy]-1,3-cyclop en -

ta n ed im eth a n ol ((+)-25a ). According to general procedure

III, to a solution of nitronates 21 (0.383 g, 0.88 mmol) in

acetonitrile (50 mL) and benzene (40 mL) was added sodium

bicarbonate (0.222 g, 2.64 mmol, 3 equiv). The suspension was

heated to reflux for 30 min and was left to stir for 10 h at

room temperature. Concentration afforded a yellow foam

which was subjected to hydrogenolysis without purification.

According to general procedure IV, NaBH₄(66 mg, 1.76

mmol, 2 equiv) was added to a solution of anhydrous nickel

chloride (114 mg, 0.88 mmol, 1 equiv) in methanol (12 mL) at

room temperature. A black precipitate formed almost im-

mediately with the concomitant evolution of hydrogen. The

nickel boride was then cooled to 0 °C, and another 2 equiv of

NaBH₄(66 mg, 1.76 mmol, 2 equiv) was added followed by

the addition of a solution of nitroso acetals 23 (0.880 mmol)

in methanol (6 mL). After ca. 10 min, the last 2 equiv of NaBH₄

(66 mg, 1.76 mmol, 2 equiv) was added. After approximately

30 min, the methanol was removed in vacuo to provide a black

solid. The crude organic concentrate was purified by silica gel

column chromatography (CHCl₃/MeOH, 10/1 (200 mL), then

CHCl₃/MeOH/NH₄OH, 10/5/1) to afford 141 mg (61% yield over

two steps) of amino diol (+)-25a as a clear oil and 113 mg (75%

yield) of recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-4).

Data for (+)-23a : ¹H NMR (499.7 MHz, C₆D₆) δ 7.96-7.94 (m,

2 H), 7.19-7.01 (m, 5 H), 7.12-7.02 (m, 3 H), 6.28 (s, 1 H),

4.18 (dd, J ) 3.1, 1.3, 1 H), 3.92-3.91 (m, 2 H), 3.75 (dd, J )

6.0, 1.3, 1 H), 3.63 (ddd, J ) 10.6, 10.4, 4.4, 1 H), 2.60-2.57

H), 6.95-6.94 (m, 2 H), 6.63-6.61 (m, 2 H), 6.00-5.99 (m, 1

H), 4.90-4.82 (m, 1 H), 4.73-4.68 (m, 2 H), 4.60 (s, 1 H), 4.12

(dd, J ) 6.4, 3.1, 1 H), 3.73-3.69 (m, 1 H) 2.72-2.69 (m, 1 H),

2.56-2.49 (m, 1 H), 1.72-0.84 (m, 10 H); TLC R_f0.29 (hexane/

EtOAc, 3/1)

(1R,6S,7S,8S,9S)-8-P h en yl-6-[(1R,2S)-(2-p h en ylcyclo-

h exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]d eca n e (22a ).

According to general procedure III, nitronate 20a (403 mg, 1.10

mmol) was added to a suspension of sodium bicarbonate (277

mg, 3.3 mmol, 3 equiv) in benzene (60 mL) and the mixture

was heated to reflux for 1 h. Purification by column chroma-

tography on neutral alumina (III) (hexane/Et₂O 5/1) provided

373 mg (87%) of nitroso acetal 22a as a 25:1 (22a /22b) mixture

1

as determined by H NMR integration. An analytical sample

of 22a was obtained by recrystallization (Et₂O): mp 112-115

1

°C (Et₂O); H NMR (499.7 MHz, C₆D₆) δ 7.18-7.14 (m, 4 H),

7.09-7.00 (m, 4 H), 6.81-6.80 (m, 2 H) 5.00 (m, 0.02 H), 4.31

(s, 1 H), 4.29 (dd, J ) 2.6, 1.8, 0.98 H), 3.98-3.92 (m, 2 H),

3.84 (d, J ) 6.0, 1 H), 3.75 (td, J ) 10.4, 4.4, 1 H), 2.73-2.69

(m, 1 H), 2.53 (ddd, J ) 12.8, 10.4, 3.7, 1 H), 1.73-1.55 (m, 3

H), 1.50-1.48 (m, 1 H) 1.42-1.34 (m, 2 H), 1.29-1.20 (m, 1

H), 1.13-1.05 (m, 1 H), 0.76 (dd, J ) 3.7, 2.2, 1 H); ¹³C NMR

(125.6 MHz, C₆D₆) δ 145.22, 140.53, 128.65, 128.34, 126.54,

126.47, 126.38, 106.08, 81.91, 81.39, 79.05, 51.89, 44.15, 40.50,

39.39, 35.11, 33.35, 32.91, 26.16, 25.40; IR (CHCl₃) 2936, 1093,

1083; MS (FAB) 392 (M⁺+ 1, 29), 159 (100); TLC R_f0.31

(hexane/EtOAc, 4/1); optical rotation [R]²⁴_D) -15.75° (c ) 1.3,

CHCl₃). Anal. Calcd for C₂₅H₂₉NO₃(391.5): C, 76.70; H, 7.47;

N, 3.58. Found: C, 76.64; H, 7.71; N, 3.41.

[(1S,3R,4S,5S)-4-(Acetyla m in o)-5-p h en yl]-1,3-cyclop en -

ta n ed im eth a n ol Dia ceta te (24). According to general pro-

cedure IV, NaBH₄(55 mg, 1.44 mmol, 2 equiv) was added to

a solution of anhydrous nickel chloride (103 mg, 0.79 mmol,

1.1 equiv) in methanol (11 mL). A black precipitate formed

almost immediately with the concomitant evolution of hydro-

gen. The nickel boride was then cooled to 0 °C, and NaBH₄

(55 mg, 1.44 mmol, 2 equiv) was added followed by the addition

of a solution of nitroso acetals 22a /b (282 mg, 0.72 mmol) in

methanol (2 mL) and ethanol (1 mL). After approximately 10

min, NaBH₄(55 mg, 1.44 mmol, 2 equiv) was added. After ca.

30 min, the methanol was removed in vacuo to provide a black

solid. Purification by silica gel column chromatography (CHCl₃/

MeOH, 10/1 (200 mL), then CHCl₃/MeOH/NH₄OH, 10/5/1)

afforded 130 mg (82%) of amino diol 24 as a 2.8/1 ratio of 24a /

24b (determined by ¹NMR integration) and 120 mg (97% yield)

of recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-4).

According to general procedure V, amino diols 24a and 24b

(221 mg, 0.0.565 mmol) were dissolved in pyridine (3 mL) and

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6193

(m, 1 H), 2.48-2.43 (m, 1 H), 2.14-2.13 (m, 2 H), 1.68-1.44

(m, 6 H), 1.39-1.30 (m, 1 H) 1.20-1.14 (m, 1 H), 1.20-1.02

(m, 1 H), 0.77 (dd, J ) 13.5, 2.4, 1 H); ¹³C NMR (125.7 MHz,

C₆D₆) δ 164.86, 145.05, 133.03, 129.83, 128.86, 128.48, 128.41,

128.31, 126.37, 110.32, 104.97, 100.19, 81.71, 80.48, 78.97,

72.40, 51.41, 43.22, 39.19, 34.83, 32.90, 32.32, 25.99, 25.35.

(4S,5R,6S)-3-Meth yl-4-ph en yl-5-(2-pr open yl)-6-[(1R,2S)-

(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H -[1,2]-oxa zin e

2-Oxid e (9e). According to general procedure II, a solution

of MAPh (3.0 mmol, 2.0 equiv) was transferred, via cannula,

to a second reaction vessel containing a -78 °C solution of

nitroalkene 8 (0.245 g, 1.5 mmol) and vinyl ether (-)-7 (545

mg, 2.25 mmol, 1.5 equiv) in CH₂Cl₂(5 mL). The resulting

dark, red-brown solution was allowed to warm slowly to -35

°C over 30 min and was then left to stir at -35 °C for 6 h (the

color faded to a light brown), after which time the reaction

was quenched with H₂O (8 mL). After an aqueous workup,

the crude material was purified by silica gel column chroma-

tography (hexane/EtOAc, 8/1 (900 mL), 5/1 (600 mL), 3/1) to

afford 376 mg of nitronate 9e and 47 mg of diastereomer 9d

for a combined yield of 423 mg (70%). The diastereofacial

selectivity of the reaction was established to be 8/1 (9e/9d ).

An analytical sample of 9e obtained after a second silica gel

column chromatography (hexane/EtOAc, 4/1). Nitronate 9d

was found to be identical by ¹H NMR to the nitronate obtained

from the SnCl₄-promoted [4 + 2] cycloaddition of 8 with vinyl

ethers (-)-6 and (-)-7. Data for 9e: 127-128 °C (hexane);

¹H NMR (499.7 MHz, C₆D₆) δ 7.12-7.11 (m, 2 H), 7.06-7.01

(m, 3 H), 6.95-6.93 (m, 3 H), 6.69-6.67 (m, 2 H), 4.89 (d, J )

2.7, 1 H), 4.81-4.72 (m, 1 H), 4.60 (d, J ) 10.0, 1 H), 4.42 (dd,

J ) 17.1, 1.0, 1 H), 3.78 (td, J ) 10.6, 4.1, 1 H), 3.18 (d, J )

11.0, 1 H), 2.82-2.79 (m, 1 H), 2.54-2.49 (m, 1 H), 1.85-1.78

(m, 1 H), 1.71-1.38 (m, 9 H), 1.32-1.22 (m, 3 H) 1.09-1.00

(m, 1 H); ¹³C NMR (125.6 MHz, C₆D₆) δ 144.95, 140.21, 135.16,

129.04, 128.86, 128.73, 128.13, 127.53, 126.62, 119.55, 116.40,

103.06, 82.67, 51.79, 47.20, 44.02, 34.63, 32.70, 26.01, 25.21,

17.51; IR (CHCl₃) 2938, 1619, 1232, 895; MS (FAB) 406 (M⁺

+ 1, 100); TLC R_f0.39 (hexane/EtOAc, 2/1); optical rotation

1

Data for (+)-25a : H NMR (499.7 MHz, CD₃OD) δ 8.06-8.04

(m, 2 H), 7.65-7.61 (m, 1 H) 7.51-7.48 (m, 2 H), 5.16-5.13

(m, 1 H), 3.81-3.65 (m, 5 H), 2.61-2.53 (m, 1 H), 2.47-2.40

(m, 1 H), 210-2.04 (m, 1 H), 1.70-1.63 (m, 1 H, H); ¹³C NMR

(125.7 MHz, CD₃OD) δ 168.11, 134.63, 131.02, 130.74,

129.68, 82.56, 63.07, 61.82, 59.36, 46.74, 42.27, 28.12; MS

(FAB) 266 (M⁺+ 1, 100); TLC R_f0.16 (CHCl₃/CH₃OH/NH₄-

OH, 10/5/1); optical rotation [R]²⁷_D) 25.3° (c ) 1.02, CH₃OH);

HRMS (FAB) Calcd for C₁₄H₁₉NO₄, 266.139233; Found,

266.139200.

[(1R,3R,4R,5R)-4-(Acetyla m in o)-5-ben zoyloxy]-1,3-cy-

clop en ta n ed im eth a n ol Dia ceta te ((-)-27a ). According to

the general procedure, the amino diol (+)-25a (118 mg, 0.44

mmol) was dissolved in pyridine (5 mL) and acetic anhydride

(5 mL) and was left to stir at room temperature for 1 h.

Purification by silica gel column chromatography (EtOAC/

hexane 2/1) provided 118 mg (68%) of analytically pure

triacetate (-)-27a as clear oil: ¹H NMR (499.7 MHz, CD₃OD)

δ 7.99 (d, J ) 7.1, 2 H), 7.56 (dd, J ) 7.5, 7.3, 1H) 4.42 (dd, J

) 7.9, 7.7, 2 H), 6.5 (d, J ) 6.8, 1 H), 5.22 (dd, J ) 9.0, 8.8, 1

H), 4.45 (q, J ) 8.8, 1 H) 5.16 (ABX, J _ab) 11.1, J _ax) 5.9, 1

H), 5.13 (ABX, J _bx) 5.6, 1 H), 4.04 (ABX, J _ab) 12.5, J _ax

)

6.9, 1 H), 4.02 (ABX, J _bx) 7.2, 1 H), 2.79-2.72 (m, 1 H), 2.56-

2.48 (m, 1 H), 2.24-2.18 (m, 1 H), 2.10 (s, 3 H), 1.92 (s, 3 H),

1.90 (s, 3 H),1.45-1.39 (m, 1 H); ¹³C NMR (125.7 MHz, CDCl₃)

δ 170.83, 170.71, 170.42, 167.08, 133.44, 129.68, 129.28,

128.43, 78.69, 64.99, 64.12, 56.87, 39.90, 35.79, 26.94, 23.04,

21.03, 20.65; IR (CHCl₃) 1737, 1733, 1276, 1245; MS (FAB)

392 (M⁺+ 1, 100); TLC R_f0.10 (EtOAc/hexane, 2/1); optical

[R]²³) 90.09° (c ) 1.05, CHCl₃). Anal. Calcd for C₂₆H₃₁NO₃

D

(405.53): C, 77.01; H, 7.71; N, 3.45. Found: C, 76.75; H, 7.74;

N, 3.32.

rotation [R]²²) -12.8° (c ) 0.68, CHCl₃); chiral HPLC

(1R ,6R ,7S ,8R ,9S)-9-Meth yl-8-p h en yl-6-[(1R ,2S)-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (10d ). According to general procedure III, nitronate

9d (418 mg, 1.03 mmol) was added to a suspension of sodium

bicarbonate (609 mg, 7.25 mmol, 7 equiv) in toluene (100 mL)

and the mixture was heated to reflux for 9 h. Purification by

column chromatography basic alumina (III) (hexane/Et₂O, 6/1)

afforded 390 mg (93% yield) of analytically pure nitroso acetal

10d as a white solid: 185 °C: ¹H NMR (499.7 MHz, C₆D₆) δ

7.67 (d, J ) 7.3, 2 H), 7.31-7.25 (m, 4 H), 7.23-7.20 (m, 2 H),

7.15-7.07 (m, 2 H) 5.07 (d, J ) 5.1, 1 H), 3.97 (td, J ) 10.4,

4.0, 1 H), 3.69 (dd, J ) 9.2, 7.9, 1 H), 2.81 (dd, J ) 7.9, 4.6, 1

H), 2.70 (d, J ) 4.6, 1 H), 2.46-2.41 (m, 1 H), 2.24 (q, J ) 5.0,

1 H), 1.89 (td, J ) 9.5, 4.6, 1 H), 1.76-1.64 (m, 3 H) 1.37-

1.18 (m, 4 H), 1.15 (s, 3 H), 1.00-0.72 (m, 3 H); ¹³C NMR (125.6

MHz, C₆D₆) δ 145.36, 137.11, 130.42, 128.54, 128.50, 128.48,

126.83, 126.22, 95.58, 79.96, 76.49, 76.15, 53.33, 51.48, 49.17,

45.89, 34.78, 30.46, 29.98, 26.23, 24.64, 21.97; IR (CHCl₃) 2934,

1079; MS (FAB) 406 (M⁺+ 1, 100); TLC R_f0.58 (hexane/

EtOAc, 2/1); optical rotation [R]²³_D) -109.4° (c ) 1.04, CHCl₃).

Anal. Calcd for C₂₆H₃₁NO₃(405.53): C, 77.01; H, 7.71; N, 3.45.

Found: C, 77.24; H, 7.77; N, 3.26.

[(1S,3R,4S,5R)-4-Am in o-4-m eth yl-5-p h en yl]-1,3-cyclo-

p en ta n ed im eth a n ol ((-)-11b). According to general proce-

dure IV, nickel chloride (123 mg, 0.95 mmol, 1.1 equiv) was

added to a solution of nitroso acetal 10e (350 mg, 0.86 mmol)

in ethanol (30 mL). NaBH₄(100 mg, 2.66 mmol, 3.1 equiv)

was added to the suspension, and after ca. 15 min, more

NaBH₄(70 mg, 1.72 mmol, 2 equiv) was added. NaBH₄(149

g, 3.9 mmol, 7 equiv) was added at various intervals through-

out the next 1.5 h. The ethanol was then removed in vacuo

providing a black solid. The crude organic concentrate was

purified by silica gel column chromatography (CHCl₃/MeOH,

10/1 (100 mL), then CHCl₃/MeOH/NH₄OH, 10/5/1) to afford

0.169 g (83% yield) of amino diol (-)-11b as a light brown solid

and 0.136 g (92% yield) of recovered (-)-(1R,2S)-phenylcyclo-

hexanol ((-)-4). The analytical data for (-)-11b, except for

the sign of the rotation, were identical to the data obtained

for amino diol (+)-11b which was derived from a tandem

sequence using MAPh as the Lewis acid in the [4 + 2]

D

(Chiralcel OD, (hexane/EtOH, 97/3), 1 mL/min); t_R(-)-27a

34.29 min (99.3%), t_R(+)-27a 43.47 min (0.7%), >98% ee.

Anal. Calcd for C₂₀H₂₅NO₇(391.42): C, 61.37; H, 6.44; N, 3.58

Found: C, 61.41 H, 6.32; N, 3.61.

(4R,5S,6R)-3-Meth yl-4-ph en yl-5-(2-pr open yl)-6-[(1R,2S)-

(2-p h en ylcycloh exyl)oxy]-5,6-d ih yd r o-4H -[1,2]-oxa zin e

2-Oxid e (9d ). According to general procedure I, tin tetra-

chloride (0.175 mL, 1.5 mmol, 1 equiv) was added to a -78 °C

solution of nitroalkene 8 (245 mg, 1.5 mmol) in CH₂Cl₂(28

mL), and the resulting bright yellow complex was left to stir

for 15 min. A solution of vinyl ether (-)-7 (485 mg, 2.00 mmol,

1.33 equiv) in CH₂Cl₂(2 mL) was added rapidly to the cold

reaction mixture via syringe. The reaction was left to stir at

-78 °C for an additional 5 min and was then quenched with

1 N NaOH/MeOH (6 mL). After an aqueous extraction, the

crude organic concentrate was purified by silica gel column

chromatography (hexane/EtOAc, 7/1 (800 mL), 6/1 (700 mL),

4/1) to afford 519 mg of 9d and 0.047 g of nitronate 9e. The

overall yield of the reaction was 0.566 g (93%) and diastereo-

facial selectivity 11/1 (9d /9e). An analytical sample of 9d was

obtained after recrystallization (hexane). Nitronate 9e was

1

found to be identical by H NMR to the nitronate 9e obtained

from a MAPh-promoted [4 + 2] cycloaddition. Additionally,

nitronate 9d was found to be identical to 9d derived from the

SnCl₄-promoted [4 + 2] cycloaddition of 8 with trans vinyl

ether (-)-6. Data for 9d : 102-103 °C (hexane); ¹H NMR

(499.7 MHz, C₆D₆) δ 7.34-7.29 (m, 4 H), 7.04-7.01 (m, 1 H),

6.95-6.94 (m, 3 H) 6.59-6.57 (m, 2 H), 5.33 (d, J ) 1.5, 1 H),

5.29-5.21 (m, 1 H), 4.86 (dd, J ) 19.2, 10.8, 2 H), 4.29 (td, J

) 10.3, 3.9, 1 H), 2.76 (d, J ) 9.0, 1 H), 2.52 (td, J ) 13.1, 3.5,

1 H), 2.11-2.09 (m, 1 H), 1.92-1.81 (m, 3 H), 1.72-1.70 (m, 1

H), 1.55-1.54 (m, 1 H) 1.46-1.44 (m, 1 H), 1.36-1.28 (m, 4

H), 1.11-0.97 (m, 3 H); ¹³C NMR (125.6 MHz, C₆D₆) δ 144.62,

140.21, 134.90, 129.00, 128.81, 128.62, 128.04, 127.49, 126.21,

118.79, 117.46, 96.08, 75.62, 51.38, 46.63, 42.13, 34.81, 33.38,

30.37, 26.28, 24.52, 17.46; TLC R_f0.30 (hexane/EtOAc, 2/1);

optical rotation [R]²³_D) -306.9° (c ) 1.03, CHCl₃). Anal. Calcd

for C₂₆H₃₁NO₃(405.53): C, 77.01; H, 7.71; N, 3.45. Found:

C, 77.04; H, 7.52; N, 3.56.

6194 J . Org. Chem., Vol. 63, No. 18, 1998

Denmark and Dixon

1

cycloaddition. Data for (-)-11b: H NMR (499.7 MHz, CD₃-

two amino diols are opposite. Data for (+)-11b: ¹H NMR (499.7

MHz, CD₃OD) δ 7.37-7.27 (m, 5 H), 3.84-3.78 (m, 2 H), 3.53

(dd, J ) 11.0, 2.4, 1 H), 3.41 (dd, J ) 11.0, 3.7, 1 H), 3.20 (d,

J ) 9.9, 1 H), 2.52-2.46 (m, 1 H), 2.20 (dt, J ) 13.2, 9.5, 1 H),

2.10-2.03 (m, 1 H), 1.91-1.84 (m, 1 H), 1.17 (s, 3 H); ¹³C NMR

(125.7 MHz, CD₃OD) δ 131.21, 130.92, 128.57, 127.18, 62.06,

61.59, 61.20, 60.75, 49.61, 41.93, 28.38, 25.96; ΙR (KBr) 3249,

2967, 2935; MS (FAB) 236 (M⁺+ 1, 100); TLC R_f0.66 (CHCl₃/

OD) δ 7.37-7.33 (m, 4 H), 7.30-7.27 (m, 1 H), 3.78 (d, J )

5.7, 2 H), 3.52 (dd, J ) 11.0, 2.4, 1 H), 3.39 (dd, J ) 11.0, 3.7,

1 H), 3.16 (d, J ) 9.9, 1 H), 2.49-2.43 (m, 1 H), 2.19 (dt, J )

13.3, 9.3, 1 H), 2.07-2.01 (m, 1 H), 1.86-1.78 (m, 1 H), 1.14

(s, 3 H); MS (FAB) 236 (M⁺+ 1, 100); TLC R_f0.66 (CHCl₃/

CH₃OH/NH₄OH, 10/5/1); optical rotation [R]²³) -23.34° (c

D

) 1.0, CH₃OH); HRMS (FAB) calcd for C₁₄H₂₂NO₂236.16505,

found 236.16510.

CH₃OH/NH₄OH, 10/5/1); optical rotation [R]²³) 23.93° (c )

D

[(1S,3R,4S,5R)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-

cyclop en ta n ed im eth a n ol Dia ceta te ((-)-12b). According

to general procedure V, the amino diol (-)-11b (13 mg, 0.057

mmol) was dissolved in pyridine (2 mL) and acetic anhydride

(2 mL) and was left to stir at room temperature for 1.0 h.

Purification by silica gel column chromatography (hexane/

EtOAc, 1/1) followed by a second silica gel column chroma-

tography (Et₂O) provided 15 mg (73%) of triacetate (-)-12b

as slightly yellow oil. The analytical data for (-)-12b, except

for the sign of the rotation, were identical to the data obtained

for triacetate (+)-12b which was derived from a tandem

sequence using MAPh as the Lewis acid in the [4 + 2]

cycloaddition. Data for (-)-12b: ¹H NMR (499.7 MHz, CDCl₃)

δ 7.33-7.30 (m, 2 H), 7.27-7.24 (m, 1 H), 7.20-7.19 (m, 2 H),

5.72 (s, 1 H), 4.40 (ddd, J ) 11.3, 6.0, 1.6, 1 H), 4.23 (ddd, J )

11.3, 7.5, 1 H), 3.79 (d, J ) 6.4, 2 H), 3.35 (d, J ) 8.8, 1 H),

2.79-2.71 (m, 1 H), 2.48-2.42 (m, 1 H), 2.18-2.12 (m, 1 H),

2.10 (s, 3 H), 1.98 (s, 3 H), 1.79 (s, 3 H), 1.71 (s, 3 H) 1.70-

1.63 (m, 1 H); ¹³C NMR (125.6 MHz, CDCl₃) δ 170.93, 170.46,

169.46, 136.83, 130.06, 128.52, 127.26, 65.21, 64.76, 63.84,

60.38, 49.22, 39.51, 31.11, 28.27, 24.30, 21.00, 20.88; TLC R_f

1.02, CH₃OH); HRMS (FAB) calcd for C₁₄H₂₂NO₂236.16505,

found 236.16510.

[(1R,3S,4R,5R)-4-(Acetyla m in o)-4-m eth yl-5-p h en yl]-1,3-

cyclop en ta n ed im eth a n ol Dia ceta te ((+)-12b). According

to general procedure V, the amino diol (+)-11b (67 mg, 0.285

mmol) was dissolved in pyridine (4 mL) and acetic anhydride

(4 mL) and was left to stir at room temperature for 1 h.

Purification by silica gel column chromatography (EtOAc/

hexane 1/1) followed by a second silica gel column chromatog-

raphy (Et₂O) provided 78 mg (76%) of triacetate (+)-29 as a

slightly yellow oil. The analytical data for (+)-12b, except for

the sign of the rotation, was identical to the data obtained for

triacetate (-)-12b which was derived from a tandem sequence

using SnCl₄as the Lewis acid in the [4 + 2] cycloaddition. Data

for (+)-12b: ¹H NMR (499.7 MHz, CDCl₃) δ 7.33-7.30 (m, 2

H), 7.27-7.23 (m, 1 H), 7.21-7.19 (m, 2 H), 5.73 (s, 1 H), 4.40

(dd, J ) 11.3, 6.0, 1 H), 4.23 (ddd, J ) 11.3, 7.5, 1 H), 3.80 (d,

J ) 6.4, 2 H), 3.35 (d, J ) 8.8, 1 H), 2.80-2.72 (m, 1 H), 2.48-

2.42 (m, 1 H), 2.18-2.12 (m, 1 H), 2.10 (s, 3 H), 1.98 (s, 3 H),

1.79 (s, 3 H), 1.71 (s, 3 H) 1.71-1.64 (m, 1 H); ¹³C NMR (125.7

MHz, CDCl₃) δ 170.97, 170.50, 169.49, 136.84, 130.07, 128.54,

127.28, 65.23, 64.78, 63.86, 60.39, 49.23, 39.51, 31.13, 28.29,

24.33, 21.00, 20.91; IR (neat) 1738, 1687, 1682, 1368, 1238,

1033; MS (FAB) 362 (M⁺+ 1, 65), 302 (100); TLC R_f0.23

(EtOAc/hexane, 2/1); optical rotation [R]²³_D) 21.72° (c ) 0.58,

CHCl₃); chiral SFC (Chiralcel OJ , 150 bar, 40 °C, 3% CH₃OH

in CO₂, 3.0 mL/min); t_R(+)-12b, 2.38 min (99.3%), t_R(-)-12b,

0.23 (EtOAc/hexane, 2/1); optical rotation [R]²³) -18.58° (c

) 1.07, CHCl₃); chiral SFC (Chiralcel OJ , 150 bar, 40 °C, 3%

CH₃OH in CO₂, 3.0 mL/min); t_R(+)-12b 2.42 min (2.5%), t_R

(-)-12b 2.78 min (97.5%), 95% ee.

D

(1S ,6S ,7R ,8S ,9R)-9-Met h yl-8-p h en yl-6-[(1R ,2S )-(2-

p h en ylcycloh exyl)oxy]-4-a za -3,5-d ioxa tr icyclo[5.2.1.0^4,9]-

d eca n e (10e). According to general procedure III, nitronate

9e (290 mg, 0.715 mmol) was added to a suspension of sodium

bicarbonate (420 mg, 5.0 mmol, 7 equiv) in toluene (70 mL)

and the mixture was heated to reflux for 14 h. Purification

by column chromatography using basic alumina (III) (hexane/

Et₂O, 6/1) afforded 250 mg (86% yield) of analytically pure

nitroso acetal 10e as a white crystalline solid: 172 °C; ¹H NMR

(499.7 MHz, C₆D₆) δ 7.51-7.49 (m, 2 H), 7.19-7.15 (m, 2 H),

7.08-7.05 (m, 1 H), 7.03-6.96 (m, 3 H), 6.84-6.82 (m, 2 H,

4.25 (d, J ) 5.1, 1 H), 4.20 (dd, J ) 7.3, 4.6, 1 H), 4.14 (dd, J

) 9.0, 7.3, 1 H), 3.30 (td, J ) 10.5, 4.3, 1 H), 2.59 (d, J ) 4.4,

1 H), 2.53-2.49 (m, 1 H), 2.38-2.33 (m, 1 H), 2.03 (td, J )

9.4, 4.5, 1 H), 1.87-1.81 (m, 2 H) 1.62-1.55 (m, 2 H), 1.47-

1.39 (m, 2 H), 1.24-0.97 (m, 7 H); ¹³C NMR (125.6 MHz, C₆D₆)

δ 145.60, 139.95, 130.19, 128.29, 128.11, 127.91, 126.58,

126.18, 102.54, 83.37, 79.76, 77.12, 53.01, 52.02, 49.91, 45.61,

35.00, 33.35, 30.20, 26.09, 25.26, 22.06; IR (CHCl₃) 2935, 1085;

MS (FAB) 406 (M⁺+ 1, 100); TLC R_f0.60 (hexane/EtOAc, 2/1);

optical rotation [R]²³_D) 25.33° (c ) 1.07, CHCl₃). Anal. Calcd

for C₂₆H₃₁NO₃(405.53): C, 77.01; H, 7.71; N, 3.45. Found:

C, 76.89; H, 7.73; N, 3.46.

[(1R,3S,4R,5S)-4-Am in o-4-m eth yl-5-p h en yl]-1,3-cyclo-

p en ta n ed im eth a n ol ((+)-11b). According to general proce-

dure IV, nickel chloride (76 mg, 0.583 mmol, 1.1 equiv) was

added to a solution of nitroso acetal 10e (215 mg, 0.53 mmol)

in ethanol (10 mL). NaBH₄(80 mg, 2.11 mmol, 4 equiv) was

added to the suspension, and after 15 min, NaBH₄(80 mg,

2.11 mmol, 4 equiv) was added. The remainder of the NaBH₄

(0.080 g, 2.11 mmol, 4 equiv) was added at various intervals

throughout the next 1.5 h. The ethanol was removed in vacuo

providing a black solid. Purification by silica gel column

chromatography (CHCl₃/MeOH, 10/1 (100 mL), then CHCl₃/

MeOH/NH₄OH, 10/5/1) afforded 100 mg (81% yield) of amino

diol (+)-11b as a light brown solid and 86 mg (94% yield) of

recovered (-)-(1R,2S)-phenylcyclohexanol ((-)-4). The ¹H

NMR, ¹³C NMR, and MS of amino diol (+)-11b were identical

to the data obtained for amino diol (-)-11b which is derived

from a tandem sequence using SnCl₄as the Lewis acid in the

[4 + 2] cycloaddition. However, the sign of the rotation of the

2.74 min (0.7%), >98% ee. Anal. Calcd for

C₂₀H₂₇NO₅

(361.44): C, 66.46; H, 7.53; N, 3.88. Found: C, 66.50; H, 7.57;

N, 3.89.

(4R,5S,6S)-4-Ben zoyloxy-5-(2-p r op en yl)-6-[(1R,2S)-(2-

ph en ylcycloh exyl)oxy]-5,6-dih ydr o-4H-[1,2]-oxazin e 2-Ox-

id e (21b). According to general procedure II, a solution of

MAPh (2.0 mmol, 2.0 equiv.) was transferred, via cannula, to

a second reaction vessel containing a -78 °C solution of

nitroalkene 19 (194 mg, 1.0 mmol) and vinyl ether (-)-7 (364

mg, 1.5 mmol, 1.5 equiv) in toluene (1 mL). The resulting dark

brown solution was left to stir at -78 °C for 2 h and was

allowed to warm slowly to 0 °C over a 4 h period. The reaction

was left to stir at -10 to 0 °C for 64 h after which time it was

quenched with H₂O (6 mL). After an aqueous workup, the

crude material was purified by silica gel column chromatog-

raphy (pretreated with Et₃N/hexane (1.5 mL/ 100 mL) (hexane/

EtOAc, 9/1 (1000 mL), 8/1) to afford 260 mg (60% yield) of

nitronates 28. Diasteremomeric ratios for the nitronates could

not be determined for this reaction due to small amounts of

decomposed products. Data for 28: ¹H NMR (499.7 MHz,

C₆D₆) δ 7.95-7.93 (m, 2 H), 7.13-7.10 (m, 1 H), 7.07-7.01

(m, 4 H), 6.97-6.94 (m, 1 H), 6.92-6.91 (m, 2 H), 6.19 (d, J )

3.1, 1 H), 5.61 (dd, J ) 8.9, 3.2, 1 H), 5.12-5.04 (m, 1 H), 4.68-

4.66 (m, 2 H), 4.60 (dd, J ) 17.1, 1.6, 1 H), 3.51 (td, J ) 10.6,

4.4, 1 H), 2.51-2.48 (m, 1 H) 2.35-2.30 (m, 1 H), 1.93-1.88

(m, 1 H), 1.73-1.67 (m, 1 H), 1.61-1.58 (m, 2 H), 1.46-1.35

(m, 3 H), 1.25-1.11 (m, 2 H), 1.03-0.94 (m, 1 H); ¹³C NMR

(125.6 MHz, C₆D₆) δ 165.58, 144.41, 134.67, 133.36, 130.03,

128.62, 128.55, 128.29, 128.10, 126.64, 116.77, 107.99, 104.53,

84.16, 68.19, 51.28, 39.44, 34.37, 33.87, 31.95, 25.76, 25.05;

TLC R_f0.29 (hexane/EtOAc, 4/1).

[(1S,3S,4S,5R)-4-(Acet yla m in o)-5-b en zoyloxy]-1,3-cy-

clop en ta n ed im eth a n ol Dia ceta te ((+)-31). To a solution

of nitronate 28 (250 mg, 0.57 mmol) in benzene (58 mL) was

added sodium bicarbonate (338 mg, 4.02 mmol, 7 equiv). The

suspension was heated to reflux for 8 h. The majority of the

sodium bicarbonate was removed by filtration through a pipet

plug, washing with benzene (15 mL). Concentration of the

Tandem Inter/Intra Cycloadditions of Nitroalkenes

J . Org. Chem., Vol. 63, No. 18, 1998 6195

filtrate afforded a yellow foam which was directly subjected

to hydrogenolysis without purification.

(dd, J ) 11.3, 5.9, 1 H), 2.88-2.80 (m, 1 H), 2.54-2.47 (m, 1

H), 2.18-2.14 (m, 4 H), 2.03 (s, 3 H), 1.96 (s, 3 H),1.44-1.38

(m, 1 H); ¹³C NMR (125.7 MHz, CDCl₃) δ 171.10, 170.87,

170.48, 167.32, 133.97, 129.68, 131.81, 128.73, 126.87, 75.74,

65.13, 62.66, 53.62, 39.96, 37.12, 29.02, 20.91, 20.90, 20.83;

IR (neat) 1737, 1732, 1226; MS (FAB) 392 (M⁺+ 1, 100); TLC

R_f0.28 (EtOAc/hexane, 2/1); optical rotation [R]²²_D) 32.11° (c

) 1.09, CHCl₃); chiral HPLC (Chirapak AD, (hexane/i-PrOH,

85/15), 1.0 mL/min); t_R(-)-31 15.5 min (0.5%), t_R(+)-31 23.00

min (99.5%), 99% ee. Anal. Calcd for C₂₀H₂₅NO₇(391.42): C,

61.37; H, 6.44; N, 3.58. Found: C, 61.57 H, 6.66; N, 3.34.

NaBH₄(86 mg, 2.28 mmol, 4 equiv) was added to a solution

of anhydrous nickel chloride (82 mg, 0.63 mmol, 1.1 equiv) in

methanol (8 mL) at room temperature. A black precipitate

formed almost immediately with the concomitant evolution of

hydrogen. The nickel boride was then cooled to 0 °C, and

NaBH₄(86 mg, 2.28 mmol, 4 equiv) was added followed by

the addition of a solution of nitroso acetal 29 (0.57 mmol) in

methanol (4 mL). After ca. 10 min, NaBH₄(86 mg, 2.28 mmol,

4 equiv) was added. After approximately 1 h, the methanol

was removed in vacuo to provide a black solid. Purification

by silica gel column chromatography (CHCl₃/MeOH, 10/1 (200

mL), then CHCl₃/MeOH/NH₄OH, 10/5/1) afforded amino diol

30 which was directly acetylated.

According to general procedure V, the amino diol 30 (0.57

mmol) was dissolved in pyridine (4 mL) and acetic anhydride

(4 mL) and was left to stir at room temperature for 1 h.

Purification by silica gel column chromatography (EtOAC/

hexane 2/1) followed by an additional by silica gel column

chromatography (Et₂O) provided 36 mg (16% yield over three

steps) of analytically pure triacetate (+)-31 as clear oil: ¹H

NMR (499.7 MHz, CDCl₃δ 7.73-7.71 (m, 2 H), 7.54-7.50 (m,

1 H), 7.47-7.43 (m, 2 H), 6.66 (d, J ) 8.1, 2 H), 5.47 (t, J )

4.8, 1 H), 4.80-4.75 (m, 1 H), 4.20 (dd, J ) 11.2, 7.0, 1 H),

4.15 (dd, J ) 11.2, 8.2, 1 H), 4.05 (dd, J ) 11.2, 6.4, 1 H), 4.01

Ack n ow led gm en t. We are grateful to the National

Institute of Health (RO1 GM-30938) for generous fi-

nancial support.

Su p p or tin g In for m a tion Ava ila ble: Experimental pro-

1

cedures along with complete H NMR, ¹³C NMR, IR, MS, and

microanalytical data for all characterized compounds (41

pages). This material is contained in libraries on microfiche,

immediately follows this article in the microfilm version of the

journal, and can be ordered from the ACS; see any current

masthead page for ordering information.

J O9802170

Article Doi

Tandem inter [4 + 2]/intra [3 + 2] cycloadditions of nitroalkenes. Asymmetric synthesis of highly functionalized aminocyclopentanes using the bridged mode (β-tether) process

DOI: 10.1021/jo9802170

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Article abstract of DOI:10.1021/jo9802170

Full text of DOI:10.1021/jo9802170

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