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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).
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