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Казанский национальный исследовательский технологический университет

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The Nitro Group in Organic Synthesis

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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.

8.3 NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION 289

INTRA

HO 7a 1

H	7	H	H
			OH

HO rosmarinecine

H OH

crotanecine

10 different necines have the cis/cis relationship

INTER

	7a	1
H	7 H	H
H	7 H	OH
		OH

HO hastanecine

macronecine

7 different necines have the trans/trans relationship

Scheme 8.41.

NO2

OG*

Oi-Pr

MAPh, toluene

i-PrO2C

SiMe2Ph

–14 ºC

SiMe2Ph

exo

73% (de > 50/1)

OG*

Raney Ni

i-PrO2C

L-Selectride

200 psi H2

SiMe

SiMe2Ph

CH2Cl2

EtOH

–78 ºC

91%

58% (95% ee)

87% recovered

SiMe2Ph

SiMe

MeSO Cl

MeSO3

TsOH, MeOH

H H

CH(OMe)3

Et3N

MeO

95% (α/β 6.0/1)

95%

MeSO3

KBr, AcO

90% TFA

AcOH, AcONa

60 ºC

MeO

81%

75%

BH3

Et3N/MeOH (2/1)

MeSO3

THF

120–130 ºC

72 ºC

71%

Scheme 8.42.

290 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

(+)-castanospermine

(+)-6-epicastanospermine

(+)-australine

(+)-3-epiaustraline

							H		1	8a O	OG*
								O		8a O	OG*
						OH		O		N
HO						OH		2	2a	8b
									2a	8b
		N					H				5a
	6				3					H O H	5a
	6		1			N		O
	7	8a	1	HO		N		O
HO				HO	2	7a				X
	8	H	OH		1	7
		H			1	7
		OH			HO	OH OH	cis	trans cis
		OH

							X = Si(t-Bu)2

O	O OG*		O	N	O	OG*
	N			N	+
[3 + 2]	[4 + 2]				+
[3 + 2]	[4 + 2]
O	O		O	Si	O
	Si			Si
t-Bu	t-Bu		t-Bu t-Bu
	OLi	+	NO2
	OLi		KO
		TfO	Cl

+Si

t-Bu t-Bu

Scheme 8.43.

predictability and control. Furthermore, the installation of functional groups at key stereocenters can be achieved by appropriate modification of dienes and dienophiles. Finally, choice of chiral auxiliary and Lewis acid sets the absolute configuration of the molecule as a whole. There are 21 structurally 7-hydroxymethyl-substituted necines. Ten of these have the all-cis relationship exemplified in (–)-rosmarinecine and could arise from tandem inter [4+2]/intra [3+2] process, as shown in Scheme 8.40. Another seven necines have the all-trans relationship, as exemplified in (–)-hastanecine and could arise from a tandem inter [4+2]/inter [3+2] process (Scheme 8.32). Examples of different necines are classified as shown in Scheme 8.41.

The synthesis of (+)-crotanecine is accomplished in 10 steps in a 10.2% overall yield, as shown in Scheme 8.42. The key step in the asymmetric synthesis is a Lewis acid-promoted, tandem inter [4+2]/intra [3+2] cycloaddition between a (fumaroyloxy)nitroalkene and chiral β-silylvinyl ether, in which the substituted silanes are used as hydroxy synthons.181

The total syntheses of the potent glycosidase inhibitors (+)-castanospermine, (+)-6-epicas- tanosperimine, (+)-australine, and (+)-3-epiaustraline have been reported. These four natural products are derived from a single common intermediate, the nitroso acetal (as shown in Scheme 8.43), which is created in the key step by the asymmetric tandem [4+2]/[3+2] cycloaddition between silaketal nitroolefin and chiral vinyl ether.182 The strategy of the synthesis is outlined in Scheme 8.43. Scheme 8.44 presents a total synthesis of (+)-castanosperimine and (+)-6-epi- castanosperimine from the common intermediate prepared by tandem [4+2]/[3+2] cycloaddition.

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