哈佛大学高等有机化学讲义Lecture32C

Prins-Pinacol methodology Prins-Pinacol syntheses Tetrahydropyran synthesis

Other uses of the Prins reaction in synthesis

I.II.III.IV.

Recent Applications of the Prins Reaction in

Stereoselective Synthesis

Eileen Shaughnessy Evans Group Seminar March 19, 1999

Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661

Prins and carbonyl ene reactions: Snider, B. B., Comprehensive Organic Synthesis , 1991, Vol. 2Bicyclic THF synthesis: Dave MacMillan, Evans Group Seminar, 1996

Approaches to 2,-6-Disubstituted THP Derivatives: Duke Fitch, Evans Group Seminar, 1997

O

R H

R 2

R 1

R 2

OH

O

O R 1

R 2

2

HX

R 1

R 2

OH X

-

Cl 4-

Cl 4+

The Prins Reaction

R 1X - >95% ee

Prins-Pinacol:

Prins:

32C-011/19/008:15 PM

OH R R OH 22

2Stereoelectronic Aspects of the Prins Reaction

from MacMillan Seminar, 1996

+ R 2CHO

- H +

Cannot undergo cyclization Can undergo cyclization

O

R

O

R Oxocarbenium Ion Formation

10 - 14 kcal/mol (E )-Oxocarbenium ion (Z )-Oxocarbenium Ion

Prins pinacol

32C-023/18/999:41 PM

-

Cl 4-

Cl 4-

Cl 4-

Cl 4O

Evidence for Prins-Pinacol Mechanism

from MacMillan Seminar, 1996

SnCl 4, CH 2Cl 2

-78 °C → -23 °C

>95% ee

enantiopure

racemic

[3,3]

aldol

Examples of Stereoselective THF Formation

422-70 → -23 °C 82%

7:1 anti:syn

BF 3?OEt 2

22 97%

422-70 → -23 °C 82%

anti

syn

from MacMillan Seminar, 1996

32C-033/18/999:51 PM

Overman: Laurenyne Synthesis

JACS , 1988, 110, 2248

EtO

OTBDPS

PPTS (cat.)CH 2Cl 2, 98%

1. SnCl 4 (2 equiv.), 0 °C, CH 2Cl 237% yield, one isomer, 4 g scale

1. (+)-DET, Ti(O i Pr)4, t BuOOH 4 ? sieves, 78%

2. Et 3NHCl, Ti(O i Pr)4, CH 2Cl 2 3:1 regioselectivity, 92%

3. TsCl, pyridine, 88%

TMS

Overman: Laurenyne Synthesis

JACS , 1988, 110, 2248

1. HF, pyridine, rt

2. PCC, NaOAc, CH 2Cl 2

3. TMSOTf, Et 3N, 0 °C, Pd(OAc)2, CH 3CN 56%

1. DIBAL

2. MsCl, Et 3N

3. NaBH 4, HMPA 65%

1. NaCN, DMSO, 95 °C

2. DIBAL TIPS

TIPS

n-BuLi, HMPA THF, -78 °C 3:1 E:Z 4. TBAF

20 steps, 0.6% yield from 1,1-TMS-Br-ethylene

32C-043/18/999:54 PM

Overman: Ring-Enlarging THF annulations

JACS, 1991, 113, 5365

1

1

1

SnCl, -70 → -23 °C

4

Overman: Ring-Enlarging THF annulations

JACS, 1991, 113, 5365 32C-053/22/999:30 AM

Overman: Ring-Enlarging THF annulations

JACS , 1991, 113, 5365

+ R 11

1

Overman: Ring-Enlarging THF annulations

JACS , 1991, 113, 5365

O

R R 2

BF 3?OEt 2 45-74%

2

1

? In reactions with ketones, only substrates with nucleophilic alkene substituents rearrange successfully.

? Acetals derived from the cis -1,2-cyclobutandiols do not undergo ring-enlarging furan annulation under a variety of conditions.

or

2R 32C-063/22/999:31 AM

Overman: Possible [3,3] rearrangement

JACS , 1991, 113, 5365

O

H

Ph

2:1 mixture of epimers

or

Two possible mechanisms explain the formation of the minor diastereomer:

Overman: Spiroannulations

Tetrahedron , 1997, 53, 8927

TMSOTf, DTBMP

22RuCl 3?3H 2O 442 68-88%

bond a

1.5:1 mixture

DTBMP = 2,6-t -butyl-4-methylpyridine 32C-073/18/9910:27 PM

Overman: Spiroannulations

Tetrahedron , 1997, 53, 8927

22RuCl 3?3H 2O 2 68-71%

TMSOTf, DTBMP 22RuCl 3?3H 2O 442 68-77%

24CH 2Cl 2, 0 → 23 °C 63%

2

NH NHC(S)NH one isomer

relative stereochemistry

established by X-ray structure

1.4:1 mixture

stereochemistry determined by X-ray structure

1.5:1 mixture

Overman: Spiroannulations

Tetrahedron , 1997, 53, 8927

1

1

1

? Axial orientation of the side chain gives good overlap in either the anti or synclinal trajectories.? If pinacol rearrangement occurs rapidly, only A and B will be formed.

? Destabilizing interactions between the SEt and the axial C-6 hydrogen in the synclinal trajectory result in the exclusive formation of the A epimer.

A

B

32C-083/22/999:47 AM

Overman: Synthesis of trans

JACS, 1991, 113, 5378

BnOCH2CHO

3

2. TBSCl

Overman: Limitations

JACS, 1988, 110, 2248

2-propyl

2-propenyl

18-24% under SnCl4 conditions

no reaction under a variety of conditions

t BuMe2

2-propyl

2-propenyl

30% under SnCl4 conditions

gives only acetal cleavage

X = Br

X = SMe

X = OAc

X = Me

R = TBS

R = TBS

R = TBS

R = Me

decomposition, acetal cleavage

TBS

TBS

? Unsaturation or heteroatoms at the β or γ positions of the acetal initiator are not tolerated in these reactions.

32C-093/22/999:40 AM

Overman: Magellanine Synthesis

JACS , 1993, 115, 2992

4CH 2Cl 2, -78 → -23 °C 57%

1. OsO 4 (cat.), NaIO 4

2. Ph 2CHNH 3Cl NaBH 3CN

i -PrOH, rt, 60%

1. Cl 3SiMe, NaI MeCN, 80 °C

2. TBSCl, imidazole DMF, rt, 76%

3. H 2, Pd(OH)2, EtOAc

4. (BOC)2O, Et 3N DMAP, 89%

2. LiMe 2Cu, TMEDA, TMSCl -78 → -23 °C

Pd(OAc)2, MeCN, CF 3CO 2H

Overman: Synthesis of trans -Kumausyne

JACS , 1991, 113, 5378

1. TMSOTf, Et 3N

2. Pd(OAc)2, 53%

3.

- 100 °C → 0 °C 88%

1. n-BuLi, NH 4Cl, 98%

2. citric acid, MeOH

3. Ac 2O, pyr., 92%

O 2. PPh 3, CBr 4

2,6-di-t -butyl pyridine benzene, 40 °C, 40%

trans -Kumausyne

32C-103/18/9910:41 PM

Overman and MacMillan: Synthesis of a Eunicellin Diterpene

JACS , 1995, 117, 10391

ds = 9:1

BF 3?OEt 2 (3 equiv.)CH 2Cl 2, -55→ -20 °C 79%

1. t -BuLi, THF, -78 °C

2. PPTS, MeOH 64%

O

OPiv

+

single stereoisomer

6 steps, 39% yield from (S )-carvone

Overman: Laurencin Model Studies

JACS , 1995, 117, 5958

BF 3?OEt 2 (2 equiv.)t -BuOMe, 0.05M -78 → -30 °C, 5h BF 3?OEt 2 (3.5 equiv.)t -BuOMe, 0.2M -78 → -10 °C, 4h +

Me 2BBr (2.5 equiv.)CH 2Cl 2, 0.05M -78 → o °C, 4h

87%40%trace

4%

7%

-

-

-

trace

32C-113/22/999:42 AM

Overman: Laurencin Synthesis

O

OAc

Et

PhS PivO

BF 3?OEt 2 (3 equiv.)-78 → -40 °C, 7h 57% ( 5 g scale)

(+)-Laurencin

24 steps, 2% yield from allyl alcohol

JACS , 1995, 117, 5958

desired product 1

A : R 1 = H, R 2 = Ac

B : R 1 = Ac, R 2 = H

By products include the THP product (7%), internal vinyl sulfide acetals (18%) and hydroxy vinyl sulfide acetates A and B

Overman: Trisubstituted Tetrahydropyrans

JACS , 1999, 121, 1092

+ RCHO (2 equiv.)

SnCl (0.5 equiv.)

MeNO 2, -25 °C 25 mM

racemic

B

A

7:3 mixture of epimers

n

32C-123/18/9910:55 PM

Overman: Trisubstituted Tetrahydropyrans

JACS, 1999, 121, 1092 racemic

Reaction of enantiopure starting material with isobutyraldehyde gives a 68% yield of A with >99% ee

Taddei: Synthesis of 4-Halo-Tetrahydropyrans

Taddei, TL, 1987, 28, 973

JOC, 1988, 53, 911

Chan,TL, 1987, 28, 3441

TMS

+ 2 RCHO

X = Cl, Br

R1CHO

1

1

O

TMSO

R2

? Aldehydes: acetaldehyde, propanal, hexanal, benzaldehyde

Yields: 43 - 86%

? Consecutive addition of different aldehydes gives unsymmetrical products. The use

of TiCl4 minimizes the formation of symmetrical halotetrahydropyrans. Yields of

unsymmetrical THPs = 41-62%

? Chan developed a similar reaction using alkoxy-allylsilanes and AlCl3, TiCl4, and SnCl4.

32C-133/18/9911:01 PM

Markó: Spiroketal Formation

TL, 1997, 38, 2895

O

R H

TMS4

CH2Cl2, 0 °C

1. NaBH4, HMPA, ?

2. HgO, I2

CCl4, ?, hν

64 - 77%

Markó: Synthesis of Okadaic Acid Model Fragment

TL, 1997, 38, 2895 Me

CHO

Me

TiCl, CH Cl, rt

NaBH4

HMPA

97%

++

CCl4, ?, hν

61%

32C-143/18/9911:06 PM

Li: InCl 3-catalyzed Prins Cyclizations

TL , 1999, 54, 1627

R

H

O R

OH

22

? This reaction compliments the TiCl 4/AlCl 3 mediated reactions which give very low yields with aromatic aldehydes.

Li: Sc(OTf)3-catalyzed Prins Cyclizations

04168eeeb8f67c1cfbd6b801m., 1999, 291

R

H

O OH

33

A

B

? Aliphatic aldehydes are less effective in this reaction.

32C-153/18/9911:10 PM

Jung: Prins Reaction Catalyzed by Silyl Triflates

JOC, 1997, 62, 9182

32

DTBMP

CH2Cl2

R1 = R2 = R3 = Me

R1 = R2 = Me, R3 = Et

R1 = H, R2 = Ph, R3 = Me

3DTBMP

CH2Cl2

no reaction

DTBMP

CH2Cl2

no reaction

Swern

R1 = H, R2 = R3 = Me

R1 = R2 = Me, R3 = Ph

89%

84%

92%

DTBMP = 2,6-di-t-butyl-4-methylpyridine

Paquette: Studies toward Trixikingolide

JOC, 1989, 54, 3334

4

22

32C-163/18/9911:15 PM

Paquette: Unsuccessful ring closure

JOC , 1989, 54, 3334

conformation adopted in the solid-state

? There was no reaction at atmospheric pressure using a variety of Lewis acids.

? Reaction at high pressure with stannic chloride polymerized the starting material.

? Conformation needed for desired cyclization:

? Aldol ring closure was also unsuccessful.

X

32C-173/22/999:25 AM

Rychnovsky: Cyclization of 4-Allyl-1,3-Dioxanes

TL , 1996, 37, 8679

i Other conditions: 1. BF 3?OEt 2, HOAc, cyclohexane 2. Ac 2O, Et 3N, DMAP Yields: 41 - 95%, > 67:33

X = Ph 60%X = F 26%, 2:1

1. BF 3?OEt 2, HOAc, benzene

2. Ac 2O, Et 3N, DMAP

C 6H Rychnovsky: Desymmetrization of C 2-Symmetric Diol

JOC , 1997, 62, 3022

1. VinylMgBr, CuI

2. CSA, CH 2Cl 2

80%

O

O

1. BF 3?OEt 2, HOAc

2. Ac 2O, DMAP, Et 3N 42-51%

O O

1. BF 3?OEt 2, HOAc

2. Ac 2O, DMAP, Et 3N 80%

1. (DHQD)2-PYR OsO 4, K 3Fe(CN)6

2.17-Deoxyroflamycoin

no antifungal activity

Influence of acetal substituent:

32C-183/19/9910:12 AM

Rychnovsky: Hemiacetal Cyclizations

TL, 1998, 39, 7271

12 DMAP 80-96%

2Bn O

R 1O Cl

CH 2Bn

I

Lewis Acid

O

Cl

C 6H 133

O

Me

C 6H 13

O

C 6 H 13O OH

Me

C 6H 13

O

OH

C 6H 13

O

Me

Cl

Cl

Cl

Cl

O

X

R 1

R

80%

79%

80%8:1

95% 7:1

65%1:1.5

90%

97%3:1

91%5:1

Using TiCl 4, CH 2Cl 2, -78 °C:

Using 1. TFAA, HOAc, CH 2Cl 2, 0 °C to rt 2. K 2CO 3, MeOH

Cl

R X-Rychnovsky: Synthesis of Model Phorboxazole Fragment

TL, 1998, 39, 7271

5H 11

DCC, DMAP

5H 11

1. DIBAL

2. Ac 2O, pyr DMAP, 81%

5H 11

SnBr 4

CH 2Cl 2, -78 °C 75%

5H 11

+

32C-193/19/9910:14 AM

Mikami: Siloxy Effect

Tetrahedron, 1996, 52, 7287

2

i-Pr

MeO2

OP

O

MeO2C H

SnCl4, CH2Cl2

-78 °C

MeO2

Proposed Transition State:

O

MeO2C H

SnCl4, CH2Cl2

-78 °C

64% yield, 4:1 cis selective

OP

O

MeO2C H

SnCl4, CH2Cl2

-78 °C

P = 2,6-dichlorobenzyl

MeO2

Mikami: Siloxy Effect

Tetrahedron, 1996, 52, 7287

2

i-Pr

MeO2

MeO2

SnCl4, CH2Cl2

-78 °C

67% yield, 3:1 cis selective

mostly ene product

2

i-Pr

MeO2

SnCl4, CH2Cl2

-78 °C

MeO2

69% yield, >95% anti selective

MeO2

SnCl4, CH2Cl2

-78 °C

32C-203/19/9910:19 AM

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