Org. Synth. 2012, 89, 267-273 267 Published on the Web 1/6/2012

© Organic Syntheses, Inc.

Discussion Addendum for:

[3 + 4] Annulation Using a [ -(Trimethylsilyl) acryloyl]silane and

the Lithium Enolate of an , -Unsaturated Methyl Ketone:

(1R,6S,7S)-4-(tert-Butyldimethylsiloxy)-6-

(trimethylsilyl)bicyclo [5.4.0]undec-4-en-2-one

OH

•

O

SiMe2But

O

Me3Si

1. ethyl vinyl ether p-TsOH, 5–10 °C

2. KOBut, 70 °C

1. n-BuLi, HMPA –80 °C

2. tBuMe2SiCl –80 ° to 0 °C

1. n-BuLi, Et2O, –80 °C2. Me3SiCl, –80 °C to rt

3. p-TsOH, MeOH, rt

O

SiMe3

TBSO

O

•

O OtBuMe2Si

OLi

THF, –80 ° to –30 °C

Prepared by Kei Takeda* and Michiko Sasaki.1

Original article: Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E.; Org.

Synth. 1999, 76, 199–213.

Brook rearrangement-mediated [3 + 4] annulation has evolved as a

unique methodology for the construction of not only seven-membered

carbocycles but also eight-membered carbo- and oxygen-heterocycles and

has been applied to the synthesis of natural products after clarification2 of

the precise reaction mechanism accounting for the stereospecificity.

Synthesis of the Tricyclic Skeleton of Allocyathin B2

The synthetic utility of annulation was first demonstrated by the

synthesis of the unusual 5-6-7 tricyclic ring skeleton of allocyathin B2, a

compound that has been shown to have potent nerve growth factor synthesis-

stimulating activity and to be a opioid receptor agonist (Scheme 1). The

key [3 + 4] annulation proceeded smoothly even with a relatively complex

four-carbon unit 1 to afford 2 as a single diastereomer in 50% yield, which

was transformed to 3.3

DOI:10.15227/orgsyn.089.0267

268 Org. Synth. 2012, 89, 267-273

Pri

Me

OLi

+THF

-80 ° to 0 °C(50%)

Me3SiO

Me3SiPri

Me

O

OSiMe3

SiMe3

DIBAL

Et2O, -80 °C(72%)

Pri

Me

OH

OSiMe3

SiMe33

1. NBS, THF

2. n-Bu4NF (72%)

Pri

Me

OH

O

H

H H

H H

H

Pri

Me

OHMe

CHO

Allocyathin B2

1 2

Scheme 1 Synthesis of the tricyclic skeleton of allocyathin B2.

Construction of a Tricyclo[5.3.0.01,4

]decenone Ring System

The use of acryloylsilanes 4 with a leaving group such as a halogen

atom at the -position as a three-carbon unit in the [3 + 4] annulation

afforded tricyclic ketone derivatives 7a,b in yields dependent upon the -

substituent of 4, in addition to the [3 + 4] annulation–debromosilylation

products 9a,b (Scheme 2).4 Small structural changes in the four-carbon unit

significantly affect the product distribution. Thus, whereas cyclopentyl

methyl ketone enolate gave 7a in almost all cases, 9b was formed as a

byproduct in the case of the corresponding cyclohexyl derivative.

Mechanistic studies including low–temperature quenching experiments

suggested that 7a,b can be formed via an SN'-like intramolecular attack of

the enolate at the C–4 position in the intermediate 6a,b, and 9a,b can be

formed via tricyclic intermediate 8a,b.

SiMe2But

Br R

O

+

O

R

tBuMe2SiO

RCH3n-Bun-hexylt-Buc-C3H5

7a6849415156

7a,b4THF

-80 ° to0 °C

( )n-4

OLi

( )n-4

9a00070

yield (%), n = 5

O

O

H

HR

9b4514171432

yield (%), n = 6

( )n-4

7b2727355839

OLi

tBuMe2SiO

( )n-4

BrR

tBuMe2SiO

O

R5a: n= 55b: n= 6

6a,b

( )n-4

8a,b9a,b

4

Scheme 2 Construction of a tricyclo[5.3.0.01,4

]decenone ring system.

Org. Synth. 2012, 89, 267-273 269

BF3 Et2O-Mediated Intramolecular Allylstannane-Ketone Cyclizations

[3 + 4] annulation using a combination of (Z)-( -

(tributylstannnyl)acryloyl)silanes 10 and alkenyl methyl ketone enolate 11

proceeded in the same manner to give cycloheptenone derivative 12, which

upon treatment with BF3 Et2O, afforded bicyclo[4.1.0]heptenols 13, an

intramolecular addition product of the allylstannane system to the carbonyl

group (Scheme 3).5

TBSO

OH

R1

R2BF3 Et2O

CH2Cl2

SiMe2But

O

SnBu3

OLi

R1R2

O

TBSO

SnBu3

R1+

R2

-30 ° to0 °C

THF

13 61–72%R1 = (CH2)4CH3, CH(CH3)2, R2 = HR1, R2 = –(CH2)–

10 11 12

Scheme 3 BF3 Et2O-Mediated intramolecular allylstannane-ketone

cyclizations.

Stereoselective Construction of Eight-Membered Carbocycles and

Oxygen-Heterocycles

The use of the enolate 15 (X = CH2) derived from 2-cycloheptenone

as the four-carbon unit in [3 + 4] annulation instead of the enolates of

alkenyl methyl ketones produced bicyclo[3.3.2]decenone derivatives 16.

The two-atom internal tether in these products could be oxidatively cleaved

after conversion to -hydroxy ketone 17 to give the cis-3,4,8-trisubstituted cyclooctenone enol silyl ethers 18 stereoselectively (Scheme 4).

6 This

methodology has also been successfully applied to the construction of

oxygen eight-membered heterocycles using enolates of 6-oxacyclohept-2-

en-1-one 15 (X = O), affording eight-membered oxygen heterocycles 18 (X = O) possessing functionality that can easily be manipulated to generate other functionalized eight-membered ring products.7

270 Org. Synth. 2012, 89, 267-273

R

OOR3Si

X

SiMe2But

O

RX

OM

X

RH

OR'3Si

OH

X

MO

R3SiO

HR

H

+1. –80 °C to rt

2.

1415

16

XR3SiOO

R 17

OHPb(OAc)4

MeOH, PhH

N CO

HPhO2S

NO2

XOM

R3SiO

R

XR3SiO

R CHO

MeO2C

18

Scheme 4 Stereoselective construction of eight-membered carbocycles and

oxygen-heterocycles.

Formal Total Syntheses of (+)-Prelaureatin and (+)-Laurallene

The versatility of the annulation has been highlighted through the

formal total synthesis of (+)-prelaureatin, a biogenetic precursor of several

members of the laurenan structural subclass (Scheme 5).8 The annulation of

19 and sodium enolate 20 proceeded in a highly diastereoselective manner to

afford exclusively 21 in 80% yield. The observed excellent selectivity could

be explained in terms of the approach of the acryloylsilane from the same

side as the C-7 substituent in 20 that is sterically less hindered because of

pseudo equatorial disposition of the substituent on the seven-membered ring.

The bicyclic derivative 21 was transformed into Crimmins’ intermediate 229

after oxidative cleavage of the two-carbon tether.

+O

OPMB

NaO

H

Me

OTBSOO

PhMe2Si

OPMB

Me

H–80 ° to–15 °C

THF(80%)PhMe2Si

O

SiMe2But

OBr

MeHO

prelaureatin

HOOPMB

Me

HTBSO

MeO2C

CHO

OBr

Me

HTBSO

HO

1920 21

7

22

Scheme 5 Formal total syntheses of (+)-prelaureatin.

Org. Synth. 2012, 89, 267-273 271

Stereocontrolled Construction of Seven- and Eight-Membered

Carbocycles Using a Combination of Brook Rearrangement-Mediated

[3 + 4] Annulation and Epoxysilane Rearrangement

The [3 + 4] annulation has also been expanded to include the

construction of densely functionalized seven- and eight-membered

carbocycles by combining it with an epoxysilane rearrangement,10

which

features a further extension of a stereocontrolled anion relay.11

Reactions of

-silyl- , -epoxy- , -unsaturated acylsilane 23 with alkenyl methyl ketone

enolate 24 afforded highly functionalized cycloheptenone derivative 28 via a

tandem process that involves Brook rearrangement followed by the resulting

carbanion-induced ring-opening of the epoxide (25 26), a second Brook

rearrangement, the formation of divinylcyclopropanediolate derivative 27

via internal carbonyl attack by the resulting carbanion, and an anionic oxy-

Cope rearrangement (Scheme 6). The reactions using an alternative

combination of three and four carbon units (29 + 30), in which an

epoxysilane moiety was incorporated in the four-carbon unit, also give

satisfactory results, via 1,4-O-to-O silyl migration (31 32). Use of

enantioenriched acylsilane 33 and 2-cycloheptenone enolate 34 gave a

moderate level (62% ee) of asymmetric induction in the bicyclic ketone 35.

272 Org. Synth. 2012, 89, 267-273

tBuMe2SiOO

OK

+THF

-80 °C, 15 min

tBuMe2SiO35 (35%, 62% ee)

OtBuMe2Si

O

SiMe2But tBuMe2SiO

tBuMe2SiO

CO2Me

CHO

O

R3Si

R'

OSiR3

R'

O

O

R'

OSiR3

R3SiO

O O

R'

OSiR3

R3SiO

+R'

SiR3O

O

SiR3O

SiR3O

O

OLi

R'

O

O SiR3

O

SiR3

R'

-80 ° to -70 °C

THF+

SiR3O

SiR3O

O

R'

SiR3O

R3SiO

-80 ° to -70 °C

THF

OSiR3

O

O

R'

R3SiR3Si

26

23 2425 26

27 28

29

3031 32

33 34

Scheme 6 Stereocontrolled construction of seven- and eight-membered

carbocycles using a combination of Brook rearrangement-

mediated [3 + 4] annulation and epoxysilane rearrangement.

1. Department of Synthetic Organic Chemistry, Graduate School of

Medical Sciences, Hiroshima University, Hiroshima 734–8553, Japan.

2. Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii,

E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947–4959.

3. Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903–1905.

4. Takeda, K.; Ohtani, Y. Org. Lett. 1999, 1, 677–679.

5. Takeda, K.; Nakajima, A.; Yoshii, E. Synlett 1996, 753–754.

6. Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031–1033.

7. Sawada, Y.; Sasaki, S.; Takeda, K. Org. Lett. 2004, 6, 2277–2279.

Org. Synth. 2012, 89, 267-273 273

8. (a) Sasaki, M.; Hashimoto, A.; Tanaka, K.; Kawahata, M.; Yamaguchi,

K.; Takeda, K. Org. Lett. 2008, 10, 1803–1806. (b) Sasaki, M.;

Oyamada, K.; Takeda, K. J. Org. Chem. 2010, 75, 3941–3943.

9. Crimmins, M. T.; Elie, A. T. J. Am. Chem. Soc. 2000, 122, 5473–5476.

10. (a) Takeda, K.; Kawanishi, E.; Sasaki, M.; Takahashi, Y.; Yamaguchi, K. Org. Lett. 2002, 4, 1511–1514. (b) Sasaki, M.; Kawanishi, E.;

Nakai, Y.; Matsumoto, T.; Yamaguchi, K.; Takeda, K. J. Org. Chem.

2003, 68, 9330–9339. (c) Sasaki, M.; Ikemoto, H.; Takeda, K.

Heterocycles 2009, 78, 2919–2941.

11. Nakai, Y.; Kawahata, M.; Yamaguchi, K.; Takeda, K. J. Org. Chem.

2007, 72, 1379–1387.

Kei Takeda is professor of organic chemistry at Hiroshima

University. He was born in 1952 and received both his B.S.

degree (1975) and M.S. degree (1977) from Toyama University

(with Eiichi Yoshii) and his Ph.D. degree (1980) from the

University of Tokyo (with Toshihiko Okamoto). In 1980, he

joined the faculty at Toyama Medical and Pharmaceutical

University (Prof. Yoshii’s group). After working at MIT with

Professor Rick L. Danheiser (1988-1989), he was promoted to

Lecturer (1989) and then to Associate Professor (1996). He

became a professor of Hiroshima University in 2000. His

research interests are in the invention of new synthetic

reactions and chiral carbanion chemistry. He was the recipient

of the Sato Memorial Award (1998) and the 41st Senji Miyata

Foundation Award.

Michiko Sasaki is an assistant professor of organic chemistry at

Hiroshima University. She obtained her B.S. degree (2002),

M.S. degree (2003), and Ph.D. degree (2006) from Hiroshima

University under the direction of Professor Kei Takeda and

then remained in Takeda’s group as an assistant professor. She

spent one year (2010-2011) at MIT as a JSPS fellow (Excellent

Young Researcher Overseas Visit Program) with Professor

Rick L. Danheiser. Her current research interests lie in the area

of development of new synthetic reactions. She was the

recipient of the Chugoku-Shikoku Branch of Pharmaceutical

Society of Japan Award for Young Scientists (2007).