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The Nitro group in organic sysnthesis - Feuer

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8.3	NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION 279
O	O				Ph		O O		OG*
N							O O		OG*
N					Ph			N
								N
	Et
H	Et					SnCl4			OAc
H		+	H	O		SnCl4			OAc
		+				- 78 ºC		Et
								Et
									OMe
			H	O					OMe
		OMe	H	O
		OMe							OMe
	OMe		O		Me				OMe
	OMe
					TsN	OH			Ph
					TsN				Ph
		1) PtO2, H2					OMe	+	Ph
		2) TsCl, DBU				Et		+	Ph
		2) TsCl, DBU				Et			(8.104)
		3) NaOH					OMe		OH
						75% (96% ee)	OMe
						75% (96% ee)			96%

A few examples of cycloadditions between nitroalkenes and vinyl ethers without the use of Lewis acids have been reported (Eq. 8.105), in which additional activating electron-withdrawing groups are generally required.161

Me
OEt	Et3N
O Ph +				(8.105)
O Ph +
O2N	RT	EtO	N
O2N	RT		N
O			O O
O			87%
			87%

High-pressure promoted cycloadditions of nitroalkenes and enol ethers eliminate the use of Lewis acids (Eq. 8.106).162 Thus, even sterically hindered nitroalkenes react with 2,3-dihydro- furan to give the exo cyclic nitronates stereoselectively without using Lewis acids.

O		O			O	O O
O	N	O				N
	N			15 kbar
			+	15 kbar	Me
Me			+	19 h		(8.106)


		Ph		O		Ph
						Ph
						60%
						60%

8.3.2 Tandem [4+2]/[3+2] Cycloaddition of Nitroalkenes

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions.

8.3.2.1 Inter [4+2]/inter [3+2] The tandem intermolecular [4+2]/intermolecular [3+2] cycloadditions create bicyclic nitroso acetals with up to six stereogenic centers, which can be controlled by the choice of the stereochemistry of each component and the Lewis acids. The nitronate derived from 2-nitrostyrene and 1-trimethylsilyloxycyclohexene reacts with methyl acrylate to give the nitroso acetal in good yield and high diastereoselectivity (Eq. 8.107).154

280 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS
	O	O D	A	O O D	O	O D
A O N O D	A	N		N	A	N

inter [4+2]/inter [3+2]	inter [4+2]/intra [3+2]		intra [4+2]/inter [3+2]		intra [4+2]/intra [3+2]
		Scheme 8.31.

However, α-substituted dipolarophiles give poor selectivity and β-substituted dipolarophiles

such as methyl crotonate fail to react.

Me3SiO

1) Raney Ni,

OMe

CO2Me

H2/KF

2) K2CO3

89% (93% de)

(14)

H Ph

73% (8.107)

Denmark and coworkers have succeeded in distinguishing the enantiofaces of achiral nitroalkenes using chiral dienophiles. For example, the nitronate shown in Eq. 8.108 reacts with methyl acrylate to give a nitroso acetal in a 7:1 mixture of two diastereomers. The structure of the major diastereomer arises as the result of a steric approach-controlled exo cycloaddition (to the face of the nitronate opposite the 3,4-dimethoxylaryl ring). Hydrogenolytic cleavage of the major nitroso acetal gives the α-hydroxy lactam in which four stereogenic centers are created with relative and absolute stereocontrol in only three steps from the simple starting materials (Eq. 8.108).160

				-O	O OG*
					N
NO2		Ph	Ph	H	OAc
		O		H	OAc
	+	O		SnCl4	Et
MeO	+			-78ºC	Et
MeO				-78ºC	OMe
OMe		OAc			OMe
OMe		OAc
					OMe
					90%
O	O	O	OG*		O
O	O	N			N
					N	OAc
MeO			OAc		HO	OAc
MeO			OAc	Raney Ni, H2	HO
CO2Me		Et		Raney Ni, H2	Et
benzene		Et
			OMe
			OMe			OMe
80 ºC						OMe
	84% (7:1)		OMe		58%	OMe
	84% (7:1)				58%	(8.108)

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (–)–hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties.164 The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that

8.3 NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION 281

O2N

MeO OMe

O O O

O N O O

MeO2C

Ti(O-iPr)2Cl2

benzene

CH2Cl2

25 ºC

MeO2C

–90

–78 ºC

OBz

71%

88% (single diastereomer)

260 psi H2

Raney Ni

PhO Cl

PhO

MeOH

DMAP

MeO2C

OBz

Pyridine

MeO2C

OBz

68% (97.7%)

82%

96%

n-Bu3SnH

LiAlH4

AIBN

MeO2C

OBz

(–)-hastanecine

87%

72%

Scheme 8.32.

undergoes simple [3+2] cycloaddition with dimethyl maleate. The resulting nitroso acetal has all the required stereocenters for (–)-hastanecine.

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied

to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165

NO2 +

OG*

MAPh

O OG*

toluene, –78ºC

G* =

20:1

CO2Me

OG*

Ph Ph

50:1

CO2Me

MeO2C

G* =

MeO2C

81%

Raney Ni, H2

LiAlH4

MeO2C

(+)-macronecine

53% (99% ee)

76%

Scheme 8.33.

282 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

Polyhydroxy pyrrolizidine and indolizidine alkaloids display a variety of interesting biological activities. The alexines,166 australines,167 and casuarines168 are a unique subset of pyrrolizidine alkaloids. The presence of a hydroxymethyl group adjacent to the ring nitrogen distinguishes this group from the larger class of necine bases. These alkaloids display glycosidase inhibitory properties169 as well as viral and retroviral suppression characteristics.170 To synthesize such polyhydroxy pyrrolizidines, the dipolarophile must contain the hydroxy functionality. Scheme 8.34 presents a total synthesis of (+)-7-epiaustraline, in which functionalized vinyl silane is used as a dipolarophile.171

Similarly, (+)-casuraline, a pentahydroxy pyrrolizidine alkaloid, is prepared by a tandem [4+2]/[3+2] cycloaddition involving nitroalkene, chiral vinyl ether, and vinyl silane. This

process creates five of the six stereocenters present in this potent glycosidase inhibitor (Scheme 8.35).172

Intermolecular [3+2] cycloadditions between cyclic nitronates and a series of dipolarophiles have been examined as discussed so far. In summary, remarkably high facial selectivity is observed which is attributed to a combination of steric shielding from the nitronate substituent and an inherent facial bias from the chiral conformation of the nitronate. Monosubstituted dipolarophiles provide cycloadducts with extensive head-to-head regioselectivity. Regioselectivity with disubstituted dipolarophiles varies with the substituents. With regard to the β-substi- tuents, head-to-tail regioselectivity is favored by O>C>Si>H. Stereoselectivity is dependent on the steric nature of the dipolarophiles. The exo approach of dipolarophiles bearing bulky substituents is generally favorable (Scheme 8.36).173

High-pressure promoted tandem [4+2]/[3+2] cycloadditions of nitrostyrenes with enol ethers has been reported, which do not require the Lewis acids. The products are converted into

N 5

17a

(+)-alexine

(+)-australine

(+)-7-epiaustraline

(+)-casuarine

O H

OG*

TDSO

benzene

TDSO

25 ºC

PhMe2Si

OBz

97% (dr = 26/1)

RO H O N

OG*

OTDS

H2 (160 psi)

TDSO

L-selectride

Raney Ni

THF, 74 ºC

PhMe2Si

OBz

MeOH

R = H (87%; dr = 14/1)

Ms2O, pyridine

PhMe2Si

OBz

R = Ms (96%)

77%

1) Hg(O2CCF3)2, TFA;

Me Me Me

HOAc-HO2Ac, 50 ºC

TDS =

2) H2, 10% Pd/C

Me Me Me

MeOH-HOAc

61%

Scheme 8.34.

8.3 NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION

283

OG*

OTDS

O2N

OBz

OG*

SiMe2Ph

TDSO

OBz

SnCl4

OBz

PhMe2Si

OBz

toluene

76% 45:7:3:2:1:1

OBz

–78 ºC

HPLC

55% 41:0:0:2:1:1

H O

OG*

1) Raney Ni,

OTDS

H2 (260 psi),

L-selectride

TDSO

OBz

MeOH

THF, – 78 ºC

PhMe2Si

OBz

2) K2CO3

R = H (87%; 10:1)

Ms2O,

PhMe2Si

R = Ms (97%)

pyridine, 1 h

64%

Hg(OTFA)2

TFA, HOAc

AcO2H

HO H OH

84%

Scheme 8.35.

a novel class of dito perform tandem acrylate.175

and tricyclic N-oxy-β-lactams (Eq. 8.109).174 High pressure is also applied [4+2]/[3+2] cycloaddition of enol ethers with nitrostyrene and resin-bound

		OR	R
		6
	O N		RO
	O		6	Facial selectivity
	O		O N	Facial selectivity
	R		O N
	R		O
	Distal-face		Proximal-face
	O	O OR	O O OR
R	O	O OR	N
R		N	N
			R	Regioselectivity
			R
	Head-to-head		Head-to-tail
		OR	OR
	O N		O N
		O	O
		H	R	Stereoselectivity
	R			Stereoselectivity
	R		H
		exo	endo

Scheme 8.36.

284 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

RO		O		O		RO	O	O
RO		O		O	15 kbar		N
	+	N			15 kbar
	+				[4+2]
					[4+2]
		Ph					Ph
NO2		Ph
NO2		RO		O	O	RO	O	O
		RO		O		RO	O
				N			N
Ph					NO2	+		Ph
15 kbar						+
15 kbar
[3+2]				Ph	Ph		Ph	NO2
				base				O
						RO	O	O
RO		O	O				N
		N	O					(8.109)
				NO2				(8.109)
							H	Ph
		H		Ph			Ph
		Ph		Ph			20–63%
		Ph					20–63%

Asymmetric tandem cycloaddition of a chiral carbohydrate nitroalkene with ethyl vinyl ether in the presence of electron-withdrawing alkenes produces a facile assembly of bicyclic systems, which can further be selectively cleaved to give homologated carbohydrates (Eq. 8.110).176

OAc OAc

AcO

OEt

CO2Et

OAc OAc

CO2Et

EtO2C

N O

EtOH

OEt

25 ºC

AcO

OEt

AcO

R* = D-lyxo-(CHOAc)3CH2OAc

(8.110)

75%

8.3.2.2

Intra [4+2]/inter [3+2]

This type of tandem reaction using nitroalkenes has not

been extensively explored, and one example has been reported (Eq. 8.111).153

CH3

O O

O N

SnCl4

RO2C

H3C

H C

H3C

-78 ºC

(8.111)

8.3.2.3 Inter [4 +2]/intra [3+2]

This type of tandem reaction using nitroalkenes has been

explored most extensively. Four subfamilies of tandem cycloaddition exist, which arise from the four different points of attachment of the dipolarophilic tether. They are defined as fused, spiro, and bridged modes, as depicted in Scheme 8.37.149

Diand trisubstituted nitroalkenes tethered to dipolarophiles (unsaturated esters, nitriles) undergo tandem [4+2]/[3+2] cycloadditions with 2,3-dimethyl-2-butene or butyl vinyl ether in the presence of Lewis acids (Eq. 8.112). For the dimethylene tether, the E-configuration of the dipolarophile is preferred, and the products arise selectively from a syn-endo pathway.177

8.3 NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION

285

N O

Me Me

SnCl4

CO2Et

O N

Me –78 ºC

20 ºC

EtO2C

68%

(8.112)

ds (> 100:1)

OBu

CO2Me

OBu

MeO2C

TiCl2 (OiPr)2

H 80% (87:13)

CH2Cl2

–70 ºC, 1 h

H2/ Raney Ni

(8.113)

80–82%

fused mode [C(4) tether]

OG*

N O

[4 + 2]

[3 + 2]

4 R3

H2C n

spiro mode [C(3) tether]

OG*

O N

OG*

[4 + 2]

[3 + 2]

H2C n

bridged mode [C(6) tether]

[X]

[4 + 2]

[3 + 2]

O O

N 1

bridged mode [C(5) tether]

O N O

OG* R

OG* [4 + 2]

[3 + 2]

OG*

O O

R1R R3

Scheme 8.37.

286 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

The synthetic potential of the tandem [4+2]/[3+2] cycloaddition process is greatly enhanced by the employment of vinyl ether dienophiles. For example, the use of vinyl butyl ether as a dienophile leads to a tricyclic nitroso acetal, which gives a tricyclic lactam, as shown in Eq. 8.113.

O N O

EtO

OEt

MeO C

MeO2C

CO2Me

TiCl2 (OiPr)2

CH2Cl2

86%

–78 ºC / 1 h (57:43)

–78 ºC / 3 h (11:89)

H2/ Raney Ni

5% NOE

84–88%

O	O	H
	O	OEt
	N	OEt
	Me	Me
	Me	H

(8.114)

O O			OG*
N			OG*
H CO2Me			Lewis acid
H CO2Me			solvent
Me			solvent
			temp
		H2/ Raney Ni
			G*OH
Me	Me
			O
OG* =			OCH But
			2
Me
		I
Chiral
vinyl		Lewis acid
ether		Lewis acid
II		Ti(OiPr)2Cl2
II		MAD
II		MAPh
I		Ti(OiPr)2Cl2
I		MAD
I		MAPh
III		Ti(OiPr)2Cl2
III		MAPh

		O	O	OG*
		O	N
EtO2C
		H	Me	H
O				O
1	N			1	N
HO			or	HO
H			H	H	Me H
H	Me		H	H	Me H
(-)-(1S)				(+)-(1R)
Ph				Ph
Ph				Ph
O				O
				O
II				III
Nitroso		Lactam		Lactam
acetal		Lactam		ee (%)
yield (%)		yield (%)		(config)
73	76			98 (1S)
88	73			72 (1S)
85	76			79 (1R)
82	86			98 (1S)
86	67			2 (1S)
83	88			99 (1R)
88	70			98 (1S)
86	74			93 (1R)

Scheme 8.38.

8.3 NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION

287

O N O

MeO2C

OEt MeO

OEt

EtO

H CO2Me

Me +

TiCl2 (OiPr)2

CH2Cl2

–70 ºC, 1–12 h

84% (α:β = 95:5)

H2/ Raney Ni

(8.115)

83%

Two simple acyclic molecules are transformed into a single tricyclic compound bearing four contiguous stereogenic centers in high yield.177

Extension of this tandem process to create five contiguous stereogenic centers has been accomplished by using 2-substituted vinyl ethers (Eq. 8.114).178 The results for the cycloaddition

	O	O	Me	OG*
	O	O		OG*
		N		(E)	O	O	OG*
			Lewis acid		O	N
	Me		Lewis acid		EtO2C
					EtO2C
							Me
MeO2C			Me	OG*	H	Me	Me
MeO2C			Me	OG*	H	Me	H
				(Z)
		Ti(OiPr)2Cl2					MAPh
					Ph		Ph
	Ph				Ph		Ph
							Ph
		CH3			O			CH
	O						O	3
						CH3
		98% ee				83% ee		74% ee
		(12/1)				(10/1)		(>50/1)
O			O		O		O
	N	Me HO		N	N		N
HO		Me HO		Me HO		Me HO		Me
H	Me	H	H	Me H	H Me	H	H Me	H
		99% ee		92% ee
		(>50/1)		(8.2/1)
Me	Me		Ph
		O		Ph
		O
	OCH2But			O
Me				CH3

Scheme 8.39.

288 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

of the same nitroalkene substrate with ethyl (Z)-1-propenyl ether or ethyl (E)-1-propenyl ether are shown in Eq. 8.114 and Eq. 8.115, respectively.

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Tiand Al-based Lewis acids) are presented in this scheme.

Extension of the enantioselective cycloaddition methods using chiral propenyl ethers is summarized in Scheme 8.39.179

The synthesis of pyrrolizidine alkaloid (–)-rosmarinecine illustrates the power of the fused mode tandem cycloaddition, as shown in Scheme 8.40.180 The all-cis relationship at the three contiguous centers C(1), C(7), and C(7a) can be constructed in a single-pot reaction with correct stereochemistry but C(6) cannot.

The tandem [4+2]/[3+2] cycloaddition of nitroalkenes is an extremely flexible method for the synthesis of necins. All of the stereochemical attributes are subject to a high level of

O					NO2				O
O
		KO		NO2
Cl				NO2		O

	OiPr CH3NO2
	OiPr CH3NO2
	O		CH2Cl2				O
	O
							69%
								H
	Li(s-Bu)3BH			PriO2C	O N		O		O
					O N

				H
	THF, –78 ºC			H		H		H
	THF, –78 ºC					H		H
				HO			O
				HO	91% (α/β 6/1)
					91% (α/β 6/1)
				O

Ph Ph		H	Ph Ph
O	O	O	O
	O	N
OiPr MAPh III	PriO2C
OiPr MAPh III	H	H H
CH2Cl2	H

	O	O
–78 ºC	O	exo

Ph Ph

160 psi H2 Raney Ni

98% recovery

74% (exo/endo 95/1)

20% (exo/endo 6.3/1)

H H H O

64%

CH(OCH3)3	HO	N	4-NO2C6H4CO2H			4-NO2C6H4CO2		N
MeOH, TsOH	HO					4-NO2C6H4CO2
MeOH, TsOH
reflux	H	H	H	Ph3P, DEAD			H	H	H
reflux		H	O	Ph3P, DEAD				H	O
	H3CO		O	THF, RT					O
				THF, RT			H3CO
		73%					H3CO
		73%					94% (97.3% ee)
				O				N
				N			HO	N
	4-NO2C6H4CO2			N			HO		H
90% TFA	4-NO2C6H4CO2					Red-Al	H
90% TFA			H		H	Red-Al	H	H
RT, 20 h			H	H	H	THF	HO	H	OH
RT, 20 h				H	O	THF	HO
			HO		O	reflux	(-)-rosmarinecine
							(-)-rosmarinecine

			87%					66%

Scheme 8.40.

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