Cyclobutane Synthesis

Myers
Chem 115
Cyclobutane Synthesis
Reviews:
• Intramolecular [2+2] Cycloadditions:
Hoffmann, N. Chem. Rev. 2008, 108, 1052–1103.
• Intramolecular [2+2] cycloadducts are readily formed. Tethers are typically 2 to 4 atom:
Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1484.
Crimmins, M. T. Chem. Rev. 1988, 88, 1453–1473.
Bach, T. Synthesis 1998, 683–703.
O
CH3
h$
Challenges:
• Cyclobutanes are highly strained:
O
hexanes
98%, dr = 92:8
OBz
H3C
O *
OBz
H3C
H
OBz
minimize non-bonded
interactions
Strain energy in kcal/mol
27.5
26.3
6.2
0.1
H3C
H3C
H
H3C
•
•
Wiberg, K. B. Angew. Chem. Int. Ed. 1986, 25, 312–322.
CH3
Synthetic Methods For the Construction of Cyclobutanes:
C6H6, 80 °C
50%
#8,9-capnellene
• [2+2] Cycloadditions:
H3C
BF3•Et2O
CH3
CH3
6 steps
H3C
CH3
H
H3C
O
epi-precapnelladiene
O
H
CH3
1. LHMDS
MeI (2 equiv)
THF
–70 " 0 ºC
2. KOH, DMSO
25 ºC, 36%
H
• Suprafacial [2+2] cycloadditions are photochemically allowed but thermally forbidden.
• Frontier Molecular Orbital Analysis:
Birch, A. M.; Pattenden, G. J. Chem. Soc., Chem. Commun. 1980, 1195–1197.
Birch, A. M.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1, 1983, 1913–1917.
• Intermolecular [2+2] Cycloadditions
• Regioselectivity issues: head-to-tail (HT) vs. head-to-head (HH)
Thermal
LUMO of one ethylene unit
Photochemical
!*
!*
O
X
HOMO of one ethylene unit
!
suprafacial [2+2]
symmetry forbidden
!*
one ethylene unit
is photoexcited
O
O
R
R
suprafacial [2+2]
symmetry allowed
• Enones are generally used as they are more easily photoexcited than isolated olefins.
h$
R
HT
HH
• Generally:
• Photoexcited enones react via the T1 (triplet excited state).
• Quantum efficiencies are higher in cyclic systems due to rapid intersystem crossing.
• Acyclic and macrocyclic enones are typically not suitable for [2+2] photocycloaddition because
upon photoexcitation, they undergo cis/trans isomerization.
HT-isomer favored when R = donor (electron donating)
HH-isomer favored when R = acceptor (electron withdrawing)
Danica Rankic
1
Myers
Chem 115
Cyclobutane Synthesis
• Ketene [2+2] Cycloadditions
• An Example of Regioselectivity Governed by Electronics
O
O
h!
H3C
H3C
H
HN
H3C
H3C
R
O
H
HN
HN
• Antarafacial [2+2] cycloadditions are thermally allowed but geometrically disfavored for most
substrates.
*
H
H3C
H3C
R
HT
R
• Ketenes are linear and sterically less encumbered, making them good substrates for thermal [2+2]
cycloadditions.
*
HH
• Frontier Molecular Orbital Analysis:
H
R
d.r. (HT : HH)
CN
18 : 82
OEt
95 : 5
O
C
C
C
O
C
• Both HT and HH products were obtained as a mixture of two diastereomers.
Suishu, T.; Shimo, T.; Somekawa, K. Tetrahedron 1997, 53, 3545–3556.
• Stereoselectivity in Intermolecular [2+2] Cycloadditions
• The least hindered transition state usually dominates. There is no "endo" effect, as in the DielsAlder Reaction:
CH3 O
H3CO2C
H3C
+
CH3 O
h!, CH2Cl2
H
CO2CH3
H3C
CH3
CH3 H
HOMO
of C=C
ketene
alkene
• Ketenes can be generated in situ from acid chlorides:
CH3
O
23 ºC, 49%
LUMO
of C=C=O
CH3
NEt3, CH2Cl2
Cl
40 ºC, 70%
CH3 O
O
O
H
CH3
CH3
O
+
CH3
O
H
CH3
HO
3.4 : 1
(separable by chromatography)
H
(+)-grandisol
Wilson, S. R.; Phillips, L. R.; Pelister, Y.; Huffman, J. C. J. Am. Chem. Soc. 1979, 101, 7373–7379.
• When the double bond is not constrained within a rigid ring system, the intermediate triplet state
diradical can lead to cis/trans isomerization of the double bond:
H3C
Mori, K.; Miyake, M. Tetrahedron 1987, 43, 2229–2239.
h!, pentane
+
23 ºC, 73%
H3C
H3C
O
H3C
CH3
h!, pentane
+
H
O
H3C
H
H3C
H
Cl3C
O
mixture of cis and
trans isomers
Cl
O
+
H3C
Zn, POCl3
Et2O, 40 ºC
78%
Cl
CH3
O
H
Cl
23 ºC, 63%
H3C
O
Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570–5583.
Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879–2882.
Danica Rankic, Fan Liu
2
Myers
Chem 115
Cyclobutane Synthesis
• A [2+2] Cycloaddition followed by radical fragmentation provided a key intermediate to
guanacastepene E:
PMP
O
O
O
O
O
h!, i-Pr2NEt
O
• Examples of [2+2] Cycloaddition in Synthesis
• Synthesis of pentacycloanammoxic acid, the principal lipid component of the cell membrane of
the anaerobic microbe Candidatus Brocadia anammoxidans:
O
h!, MeCN
O
i-Pr
1. (COCl)2, DMF
CH2Cl2, 23 ºC
4 steps
–15 ºC, 78 ºC
CO2H 2.
CH3
Et2O, 82%
CH3
i-Pr
BrCCl3, 75 ºC,
DMAP
h!, 10 ºC, 79%
t-BuOK
DMSO
50 ºC, 84%
O
O
H
i-Pr CH3
O
5 steps
CH3
• A late-stage coupling reaction provided access to biyouyanagin A:
h!, MeCN
23 ºC, 50%
Ph(H3C)2Si
pentacycloanammoxic acid
H
CH3
H3C
Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119.
CH3
• A [2+2] cycloaddition/anionic oxy-Cope/electrocyclic ring opening cascade provided a key
intermediate to periplanone B. Note that both diastereomers from the [2+2] cycloaddition step can
be converted to the final product:
O
CH3
CH3
H2C
•
H
72%, dr = 2:1
CH3
H CH
3
CH2
CH3
CH3
2. C6H6, h!
70–75%
O
CH3
CH3
2'-acetonaphthone
25 ºC, 46%
H
H3C
CH3
H H
H Ph
O CH3
O
O
O
• A [2+2] photocycloaddition followed by acid-catalyzed rearrangement provided a key intermediate
to steviol:
2. KH, 18-C-6
THF, 60 ºC
75%
1. toluene, 175 ºC
h!, CH2Cl2
O
O
Ph
O
h!, CH2Cl2
H3C
HO
O
H
H
H3C
O CH3
Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708–4711.
1. Et2O,
MgBr
–78 ºC, 63%
O
h!, Et2O
CH3
Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025–7035.
Si(CH3)2Ph
(CH2)7CO2CH3
O
i-Pr H C
3
guanacastepene E
O
PMP
O
OH
AcO
O
12 steps
CH3
1. SmI2, HMPA
THF, 23 ºC
2. PhSeBr, 50%
3. mCPBA, CH2Cl2
–78 ºC, 86%
Br
N
S
ONa
H3C
PMP
H2C
O
CH3
CH3
O
CH3
•
H3C
23 ºC, 82%
CH3
HO
CH2
3. AcOH, PPA
110 ºC, 62%
H3C
HO
1. O3, MeOH
–78 ºC
2. Me2S, 23 ºC
O
CH3
O
Schreiber, S. L.; Santini, C. J. Am. Chem. Soc. 1984, 106, 4038–4039.
Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem. Int. Ed. 2013, 52, 9019–9022.
Fan Liu
3
Myers
Chem 115
Cyclobutane Synthesis
• The synthesis of longifolene was accomplished via a de Mayo reaction –– a [2+2] cycloaddition
followed by retro-Aldol fragmentation:
• In the synthesis of ginkgolide B, three contiguous stereogenic centers were established using an
intramolecular ketene [2+2] cycloaddition reaction:
H3CO
OCbz
OCbz
O
h", C6H12
H2, Pd/C
15–30 ºC, 83%
dr = 2:3
AcOH, 25 ºC
83%
H3C
O
O
O
Ph3C
O
2. n-Bu3N, toluene
110 ºC, 71–87%
H
CO2H
O
H
O
O
HO
H OH
O
O
Longifolene
H
O
O
steps
O
O
H3C HO
O
H
H3C
O
H
t-Bu
OH
Ginkgolide B
Corey, E. J.; Kang, M.-C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649–
651.
Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583–2584.
• Synthesis of clovene via a ketene [2+2] thermal cycloaddition:
1.
H
Et3N, CH3CN
80 ºC, 35–47%
CO2H
OH
1N NaOH
acetone
–30 ºC, 86%
H
H3C PPh3
Br–
NaOt-amyl
toluene, 25 ºC
88%
CH3
N
Cl
CH3
O
H
4 steps
CH3
O
1. (COCl)2, C6H6
23 ºC
CH3
• Synthesis of retigeranic acid via a ketene [2+2] cycloaddition followed by cyclobutane ring
expansion:
Li
SCH3
H3CS
SCH3
CO2H
CH3
H
SMe
SMe
THF, –78 ºC
O
H3C
H
H3C
2. HCl, CHCl3
66%
O
H3C
H3C
1. (COCl)2, C6H6, 23 ºC
H3C
H
H
2. Et3N, 23 ºC, 80 %
H
CH3
H3C
H
CH3
Li
1.
CH3
H
H3C
H3C
clovene
1. H2NNHTs, MeOH
2. BuLi, TMEDA;
H3O+, 55%
CH3
H
H3C
H3C
1. NaH, MeI,
DME, 75%
2. Raney Ni,
acetone, 79%
O
Bamford-Stevens-Shapiro Reaction
H3C
H3C
H
CH3
H
H3C
H
CH3
CO2H
H
CH3
H3C
5 steps
H3C
H
H
CH3
H
H3C
H
CH3
O
retigeranic acid
Funk, R. L.; Novak, P. M.; Abelman, M. M. Tetrahedron Lett. 1988, 29, 1493–1496.
O
Corey, E. J.; Desaid, M.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339–4341.
SCH3
SCH3
THF, –78 ºC
73%
2. CuOTf, Et3N
C6H6, 23 ºC
3. NaIO4, H2O
dioxane
4. Al/Hg, THF
H2O, 0 ! 23 ºC
Fan Liu
4
Myers
Chem 115
Cyclobutane Synthesis
• Formal [2+2] Cycloadditions: Michael-Aldol Mechanism
• Silyl enol ethers and !,"-unsaturated compounds form cyclobutanes in a stepwise, Lewis acidcatalyzed process.
• Upon activation by triflic anhydride, C2-symmetric chiral pyrrolidine amides form keteniminium
salts, which undergo thermal [2+2] cycloadditions with excellent stereoselectivities:
• In the following example, the bulky tris(trimethylsilyl)silyl (TTMSS) protecting group is required to
stabilize the cationic intermediate. This and the use of a bulky aluminum catalyst with the triflimide
counterion suppress silyl transfer:
O
Tf2O, DTBMP
N
Ph
O
TTMSSO
N
C
TfO– CH3
TTMSSO
H
1. 20 # 83 ºC
2. H2O, CCl4
80 ºC, 88%
98% ee
O
Ph (1 mol%)
OPh
ClCH2CH2Cl
H3C
O )2AlNTf2
H3C
CH3
OPh
O
H
CH2Cl2, –40 ºC
82%, dr = 10:1
Chen, L.; Ghosez, L. Tetrahedron Lett. 1990, 31, 4467–4470.
LA
LA
O
TTMSSO
• (–)-Phenylmenthol was also found to be an effective chiral auxiliary in formal [2+2] cycloadditions
of silyl enol ethers and acrylates:
O
OPh
TTMSSO
OPh
CH3
CH3
O
OTBS
O
+
H3C
Boxer, M. B.; Yamamoto, H. Org. Lett. 2008, 7, 3127–3129.
CH
Ph 3
Ph
H3C
EtAlCl2 (20 mol%)
O
AlCl2Et
O
CH2Cl2, –78 ºC
H3C
• Auxiliary-Controlled Stereoselective [2+2] Cycloadditions
TBSO
• One of the earliest reports involved the use of (–)-phenylmenthol as a chiral auxiliary to achieve a
diastereoselective [2+2] cycloaddition:
CH3
H3C
110 ºC, 70%
Ph
CH3
CH3
H3C
Ph
O
Cl3CCOCl
Zn-Cu, Et2O
20 ºC, >70%
67% dr
H3C
•O
CH3
CH3
O
i-Pr
OTBS
+
H3C
Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525–5528.
33%, >99% de
CH3
OH
CH3
H
51%, >99% de
Cl
Cl
O
OR*
+
H
O
H
TBSO
OR*
Ph
OCH3
TsOH, PhCH3
OCH3
O
CH3
EtAlCl2 (20 mol%)
O
H3C
CH
Ph 3
CH2Cl2, –78 ºC
TBSO
i-Pr
H3C
CH3
O
OR*
91%, >99% de
Takasu, K.; Nagao, S.; Ueno, M.; Ihara, M. Tetrahedron 2004, 60, 2071–2078.
Takasu, K.; Ueno, M.; Inanaga, K.; Ihara, M. J. Org. Chem. 2004, 69, 517–521.
Fan Liu, Danica Rankic
5
Myers
Chem 115
Cyclobutane Synthesis
• Enantioselective [2+2] Cycloadditions with Lewis Acid Catalysts
• The reaction is proposed to occur by an asynchronous process. The structures shown below were
presented to rationalize the stereochemical outcome:
• In early reports, taddolates were found to catalyze formal [2+2] cycloadditions:
O
N
H3CO
O
O
H3CS
SCH3
+
CO2CH3
TiCl2(Oi-Pr)2
I (10 mol%)
4Å MS, –78 ºC
toluene
petroleum ether
O
N
H3CS
H3CS
O
O
O
Ph
96%, 98% ee
H3C N B
Br3Al
O
Ph Ph
H3C
O
OH
Ph
O
OH
F3CH2CO
Ph
H3C N B
Br3Al
O
O
H
H
H
!+
O
O
H
F3CH2CO
H H
H
Ph Ph
I
O
O
O
H3CO
N
O
(H3C)3Sn
+
O
SCH3
C
H
H
TiCl2(Oi-Pr)2
I (10 mol%)
N
H3CO2C
O
• Transformations of the cyclobutane products:
O
Sn(CH3)3
SCH3
4Å MS, 0 ºC
toluene
petroleum ether
93%, 96% ee
dr > 20:1
Hayashi, Y.; Narasaka, K. Chem. Lett. 1989, 793–796.
Hayashi, Y.; Niihata, S.; Narasaka, K. Chem. Lett. 1990, 2091–2094.
OCH2CF3
O
OCH2CF3
+
II (10 mol%)
O
H
H
O
OCH2CF3
N
Br3Al
CH2Cl2, –78 ºC
H
87%, 99% ee
dr > 99:1
B
O
+
TIPSO
OCH2CF3
II (10 mol%)
O
TBSO
CH3
CH3
TBAF, THF
0 " 23 ºC
Ph
Ph
O
CH3
O
II
NaOH, MeOH
23 ºC, 80% (2 steps)
CH3
OTIPS
1. CH3ONHCH3•HCl
CH3MgBr
THF, –30 ºC
2. CH3MgBr, THF
–30 " 0 ºC, 85%
CH3
• An aluminum bromide oxazaborolidine complex was found to be a highly efficient catalyst:
O
O
TBSO
OH
O
CH3
CH3
O
OCH2CF3
CH2Cl2, –78 ºC
H
Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687.
99%, 99% ee
dr = 99:1
Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687.
Fan Liu
6
Myers
Chem 115
Cyclobutane Synthesis
• Photoredox Catalysis
• Cis-olefins are isomerized during the course of the reaction:
• Photoredox catalysts absorb light in the visible region and provide a pathway for cyclization
mediated by electron transfer rather than direct photoexcitation of the substrate:
OCH3
5 mol% Ru(bpy)3(PF6)2
15 mol% MV(PF6)2
Ph
MeO
Ph
H
H
Ph
visible light
MgSO4, MeNO2
71%, dr = 6:1
O
H3CO
O
MV2+ = methyl viologen (N,N'-dimethyl-4,4'-bypyridinium)
H3C N
H3CO
Ph
visible light
MgSO4, MeNO2
88%, dr >10:1
O
5 mol% Ru(bpy)3(PF6)2
15 mol% MV(PF6)2
H
H
O
• Limitation of the method: at least one of the styrenes must bear an electron-donating substituent
at the para or ortho position. Aliphatic olefins are not suitable reaction partners.
N CH3
• Mechanism:
*Ru(bpy)32+
strong
reductant
visible light
• Photoredox catalysis can also be used for [2+2] cycloadditions of enones:
N CH3 (MV2+)
H3C N
Me N
+1 e-
N Me
Ph
(MV-radical)
Ru(bpy)32+
photocatalyst
O
O
Ph
product
Ru(bpy)33+
strong oxidant
visible light
Ru(bpy)3Cl2 (5 mol%)
O
O
H
H
Ph
Ph
LiBF4, i-Pr2NEt
MeCN, 89%, dr >10:1
MV2+
-1 e-
+1 e–
OCH3
p-CH3OC6H4
MV-radical
Ph
OR
p-CH3OC6H4
O
O
Ph
H
H
O
O
Ph
CH3
CH3
visible light
Ru(bpy)3Cl2 (5 mol%)
LiBF4, i-Pr2NEt
MeCN, 84%, dr >10:1
O
Ph
O
CH3
H3C
• Upon photoexcitation, the photocatalyst (Ru(bpy)3(PF6)2) acts as a strong reductant, reducing MV
by a single electron.
• The resulting Ru(III) species acts as a strong oxidant, which oxidizes the electron-rich styrene to
produce a radical cation and regenerates photocatalyst.
• The resulting radical cation undergoes cyclization.
Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572–8574.
Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887.
Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605.
Danica Rankic
7
Myers
Chem 115
Cyclobutane Synthesis
• Mechanism:
• An intramolecular variant was also developed.
• The product can be converted to acids, esters, thioesters and amides:
visible light
*Ru(bpy)3
2+
i-Pr2NEt
Li
O
LiBF4
Ph
Ru(bpy)32+
O
N
i-Pr2NEt
+1 e–
Ru(bpy)3+
Li
–1 e–
CH3
O
N
O
visible light
Ru(bpy)3Cl2 (2.5 mol%)
OBn
LiBF4, i-Pr2NEt
MeCN, 87%, dr >10:1
O
Ph
Ph
Me
CH3
Me
O
O
O
H
H
BnHN
CH3
O
O
N H
H
H3C
N
OBn
1. MeOTf, CH2Cl2
67%
2. BnNH2, DBU
CH2Cl2, 98%
OBn
98%, dr >10:1
Li
O
O
Ph
–1 e–
CH3
Ph
H3C
Li
O
O
CH3
H3C
Tyson, E. L.; Farney, E. P.; Yoon, T. P. Org. Lett. 2012, 14, 1110–1113.
O
O
Ph
CH3
• Styrenes and alkenes undergo [2+2] cycloaddition in the presence of an Ir catalyst (III) and light.
The catalyst functions as a photosensitizer.
H3C
CF3
F
• Lewis acid coordination decreases the reduction potential of the enone, facilitating single electron
transfer.
• Limitation of the method: one coupling partner must be an aromatic ketone. Aliphatic ketones and
esters do not under go cycloaddition because of their higher reduction potentials.
Ph
CH3
visible light
III (1 mol%)
CH3
CH3
H
Ph
CH3
H
DMSO, 83%
O
N
F
OH
EtO2C
H3C
O
H3C
N
N
visible light
Ru(bpy)3Cl2 (2.5 mol%)
O
CH3
i-Pr
LiBF4, i-Pr2NEt
MeCN, 73%, dr >10:1
H3C
N
O
CH3
F
N
N
O
F
CH3
O
CH3
EtO2C
DMSO, 86%
H3C
t-Bu
CF3
III
H3C CH3
H
H
•
O
CH3
O
CH3
N
i-Pr
HO
visible light
III (1 mol%)
PF6–
IrIII
Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887.
Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605.
• !,"-Unsaturated 2-imidazolyl ketones also undergo photochemically induced cycloadditions:
t-Bu
N
HO
HO2C
H3C
H3C CH3
H
H
•
O
LiOH
60 ºC
97%
CH3
(±)-cannabiorcicyclolic acid
Lu, Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2012, 51, 10329–10332
Danica Rankic
8
Myers
Chem 115
Cyclobutane Synthesis
• Other Methods for Cyclobutane Synthesis
• Gold(I)-Catalyzed Ring Expansion of Cyclopropanes
• Brook Rearrangement of 1,4-Dicarbonyls
• Alkynyl cyclopropanols can undergo ring expansion upon treatment with catalytic Au(I):
• Treatment of keto acylsilanes with organolithium reagents produces highly functionalized
cyclobutanes favoring cis-stereochemistry between newly formed alcohols
t-Bu
PhLi, THF
i-Pr
TBS
O
O
–80 " –30 ºC
TBSO
Ph
OH
i-Pr
HO
Ph
67%
HO
OTBS
[(p-CF3C6H4)3P]AuCl (0.5 mol%)
AgSbF6 (0.5 mol%)
O
CH2Cl2, 23 ºC, 98%
i-Pr
single isomer
10%
Mechanism:
• The mechanism is proposed to involve a stereospecific 1,2-alkyl shift:
i-Pr
TBS
O
Ph
O
TBSO
Ph
i-Pr
O TBS O
OH
i-Pr
Ph Li
[(p-CF3C6H4)3P]AuCl (1 mol%)
AgSbF6 (1 mol%)
Ph
O
TBSO
CH2Cl2, 23 ºC, 94%
Brook rearrangement
H3C
H3C
CH3
AuL
• Ring Expansion of Cyclopropanes via Pinacol-Type Rearrangements
TBSO
• Hydroxycyclopropyl carbinols can be ring-expanded by treatment with protic or Lewis acids.
H3C
• Either cis- or trans-substituted cyclobutanones could be produced from a single diastereomer of a
an !-hydroxycyclopropyl carbinol:
BF3•Et2O
(20 mol%)
O
n-Bu
80%
17:1 cis:trans
concerted
migration proposed
THF, 23 ºC
HO
Ph
CH3
H+
Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705–3707.
Ph
t-Bu
p-TsOH•H2O
(10 mol%)
O
CHCl3, 23 ºC
Ph
Ph
AuL
O
CH3
H3C
Ph
CH3
Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709.
n-Bu
Ph
OH
single diastereomer
n-Bu
94%
1:17 cis:trans
thermodynamic
product
Hussain, M. M.; Li, H.; Hussain, N.; Urena, M.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2009, 131, 6516–6524.
Danica Rankic
9
Myers
Chem 115
Cyclobutane Synthesis
• Cu-catalyzed 1,4-Ring closure
• The products can be derivatized:
• Homoallylic sulfonates can undergo borylation/cyclization using a CuI catalyst:
Bn(H3C)2Si
OMs
Ph
CuCl (5 mol%)
dppp (5 mol%)
Ph
B2pin2, KOt-Bu
THF, 23 ºC
H3C CH
3
CH3
O
B O CH3
O
CH3
CH3
CH3
CH3
O
B B
O
O
B2pin2
CuCl (5 mol%)
dppp (5 mol%)
(H3C)2PhSi
OMs
(H3C)2PhSi
H3C
H3C
H3C
H3C
H3C CH
3
CH3
O
B O CH3
1. TBAF, THF
23 ºC
2. H2O2, KHCO3
CH3OH, 23 ºC
OBz
49% (2 steps)
(dppp)Cu
(dppp)CuI-Bpin
R2
OBz
Bpin
H
R1
OMs
+KOt-Bu
Bpin
HO
OMs
(dppp)CuIOt-Bu
R1
OBz
R1
pinB Ot-Bu
pinB!Bpin
OBz
HO
1. TBAF, THF
23 ºC
2. H2O2, KHCO3
CH3OH, 23 ºC
57% (2 steps)
R2
R2
Bn(H3C)2Si
2. PhCOCl, C5H5N
CH2Cl2, 0 ºC
61% (2 steps)
1. LiCH2Cl, THF
–78 " 23 ºC
2. H2O2, NaOH
THF, 0 ºC
3. PhCOCl, C5H5N
CH2Cl2, 0 ºC
73% (3 steps)
R3Si
1. H2O2, NaOH
THF, 0 ºC
B2pin2, KOt-Bu
THF, 23 ºC
• Mechanism:
CuCl
BPin
R2
R1
R2 Bpin
H
tBuO CuIII
dppp
R1
t-BuO
K+
CuI
dppp
Bpin
Ph
BPin
1. BCl3, CH2Cl2
23 ºC
Ph
NHBn
2. BnN3, CH2Cl2
0 ºC, 57%
• Note that in each case the stereochemistry of the starting material is preserved in the product.
H
OMs
KOMs
• Limitation of the method: only aryl- or silyl-substituted olefins react; alkyl olefins do not undergo
borocupration.
Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990–5992.
Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709.
Danica Rankic
10

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