Higher Order Cycloadditions in Synthesis
O'Malley
Group Meeting
8/30/2006
Notes on Mechanism
The cyclodimerization of alkenes and alkynes is a fundamental transition metal
mediated process. This is the basic step in the mechanism of metal catalyzed or
mediated higher order cycloadditions. For a detailed discussion, see
Hegedus, L. Transition Metal in the Synthesis of Complex Organic Molecules,
University Science Books, 1999.
MN+2
MN
Depending on the nature of the metal, this metallocycle can undergo many different
reactions. For the purposes of this presentation, the most relevant are insertion
reactions of alkenes, alkynes, and carbon monoxide to form expanded metallocycles.
These metallocycles can then undergo reductive elimination to regenerate the active
catalyst.
MN+2
MN+2
MN+2
-MN
Although the mechanisms of some higher order cycloadditions have not been
exhaustively studied, it is believed that cyclization/insertion processes are generally
responsible for these reactions.
A further mechanistic point regarding metal mediated reactions is that photolysis
is frequently used to aid in the dissociation of carbonyl ligands from metal centers.
In metal mediated cycloadditions, irradiation is frequently used for this purpose, rather
than to initiate a photochemically allowed concerted cycloaddition.
Group Meeting
8/30/2006
Group Meeting
8/30/2006
Higher Order Cycloadditions in Synthesis
O'Malley
1. LDA,
O
[2+2], [3+2], and especially [4+2] cycloadditions are well established methods for ring
synthesis. By contrast, the synthesis of larger rings through higher order cycloaddition
reactions is far less common. Due to the breadth of this topic, this presentation is far
from exhaustive and focuses mainly on synthetic applications of higher order
cycloadditions.
O
(EtO)2(O)P
EtO
CH2OH
OEt
Tf2O, 2,6-lutidine
DCM, -78 °C
32 %
OEt
2. LiAlH4
69%, 1:1
OMOM
OMOM
Some general references:
Evans, P.A, ed. Modern Rhodium-Catalyzed Chemistry, Wiley-VCH, 2005.
Yet, L. "Metal-Mediated Synthesis of Medium-Sized Rings" Chem. Rev. 2000, 100,
2963-3007.
Mehta, G.; Singh, V. "Progress in the Construction of Cyclooctanoid Systems: New
Approaches and Applications to Natural Product Synthesis" Chem .Rev. 1999, 881-930.
O
O
Me
Me
H+
42%
H
H
CH2OMOM
(+)-aphanamol
[4 + 3] Cycloadditions
The initial report of a [4+3] cycloaddition came from Fort (JACS, 1962,4979-4981).
Furan was used to capture the oxallyl species generated from chlorodibenzyl ketone.
Ph
Ph
OMe
PhO2S
BuLi, THF;
PhO2S
SPh
Ph
Ph
SPh
O
I
TiCl4 (inverse addn.)
-78 °C, 86% 1:1.1
O
O
DMF, rt, 18%
Cl
OMe
O
2,6-lutidine,
furan
O
CH2OMOM
-78 °C to rt, 83%
This reaction was adapted for the synthesis of thromboxane analogs.
(Bowers and Mann, Tet. Lett. 1985, 26(36) 4411-4412.
O
O
O
Ph
Br
O
+
26 %
(incl.bromination)
(15 eq)
O
(+)-widdrol
Lautens has demonstrated the enantioselective opening of furan [4+3] adducts. JACS,
1997, 119, 11090-1.
OP
O
R
O
R OP
C5H11
OH
The intramolecular version of this reaction has been studied extensively with a range
of precursors oxyallyl species. Harmata et. al. Tet. Lett. 1997, 38(46), 7985-7988;
Tetrahedron, 1997, 53(18), 6235-6280; Acc. Chem. Res. 2001, 34, 595-605.
CN
CHO
CN
OMOM
+
Ni(COD)2, (R)-BINAP
85%
58%
Li
OMOM
R
R
OH
DIBAL
80-100% and >95% ee for multiple substrates, also
works for adducts diastereomeric to the one shown.
Trost has shown that trimethylene methane equivalents can undergo [4+3] cyclization
with dienes. Due to the stepwise mechanism of this reaction, competing [3+2] reactions
can pose a problem. Chem. Lett. 1994, 2245-2248.
MeMgI
(EtO)2(O)P
OH
O
CH(OMe)2
(CH2)CO2H
O
+
O
SPh
Ph
TFE, NEt3
CH(OMe)2
O
SPh
O
O
TMS
OCOtBu
CO2Me
O
O
CO2Me
Pd(OAc)2/P(OiPr)3/BuLi,
THF, 60 °C, 6h
48% (+33% [3+2])
1
Group Meeting
8/30/2006
Higher Order Cycloadditions in Synthesis
O'Malley
Fischer vinylcarbenes undergo formal [4+3] cycloadditions with a variety of dienes and
hetero dienes. It is important to note that these reactions actually proceed via a [2+1]
addition followed by Cope rearrangement of the resulting diallyl cyclopropane. This
reaction is included here because the Cope rearrangement usually occurs at room
temperature and the formal [4+3] adduct is obtained directly (Barlunga et. al. JACS,
1995, 117(37), 9419-9426; J. Chem. Soc. Chem. Comm. 1994, 321-2).
OH
OAc
O
TBSO
OAc
DBU, MeCN
H
O
88%
O
OAc
OH
H
O
O
Cr(CO)3
N
MeO
MeO
MeCN, rt;
OMe
O
O
3 N HCl, 45%
86% ee
OMe
O
OMe
O
R2 N
Li, 1% Na
Br
NHtBu
OMe
Ph
hυ, 70% (1:1)
Et2O, NH3, 87%
NHtBu
90%
MeO
Li, MeNH2, 66%
N
[5 + 2] Cycloadditions
(+)-siliphinene
The participation of 3-oxidopyriliums on [5+2] cyclodditions was initially reported in 1962.
(Ullman, E. F.; Milks, J. E., JACS, 1962, 84, 1315-6). Wender used an intramolecular
version of this reaction in his syntheses of Phorbol and Resniferitoxin (JACS, 1997, 119,
7897-8, 12977-8).
O
OTBS
OBn
O
1. NBH4, 0 °C, 100%
2. mCPBAA, 0 °C, 100%
3. Ac2O, DMAP, py
0 °C, 100%
Wender has developed rhodium catalyzed [5+2] cycloadditions of vinylcyclopropanes
with a variety of 2π components. Intramolecular cycloaddition with an allene served as
the key step in the syntheses of (+)-dictamnol and (+)-aphanamol I. (Org. Lett. 1999,
1(1), 137-9; 2000, 2(15), 2323-6).
O
O
OBn
DBU, MeCN
(EtO)2(O)P
N
80 °C, 84%
O
OAc
OTBS
OMe
•
H
OBn
O
O
OTBS
O
OTBS
O
I
2. DMP, DCM, 80%
HO
H
MeMgBr, 0 °C, Et2O
O
OBn
tBuLi, Et2O,
-78 °C to rt, 82%
1. [Rh(CO)Cl]2 (2.5%)
DCE, 80 °C, 7 h, 76%
CBS red.
O
Ph
OMe
•
OAc
OAc
O
N
2 h, 90%
78%, 91% ee
OAc
O
cPrCHO, NaH
•
O
OH
SiO2, THF-Et2O, rt, 3h
NH
OAc
Phorbol
Arenes undergo [5+2] cycloadditions with olefins under photochemical conditions. This
served as the basis for Wender's three step synthesis of siliphinene. (Tet. Lett. 1985,
26, 2625). For a more complete treatment of this reaction, see the group meeting
presentation "Cyclopentane Synthesis" and Wender, P. A.; Siggel, L.; Nuss, J. M. "[3+2]
and [5+2] Arene-Alkene Photocycloadditions" in Comprehensive Organic Synthesis,
Trost, B. M. ed. Volume 5, 645-673.
O
Cr(CO)3 THF, -78 to -40°C, 3h;
H
O HO
OTBS
MeO
OH
50% 1:1 dr
O
HO H
O H
(+)-dictamnol
O
OMe
O
O
•
[Rh(CO)Cl]2 (0.5%)
PhMe, 110 °C, 0.5 h,
OH
(+)-Resniferitoxin
OBn
93%
H
H
OBn
OH
(+)-aphanamol
2
Wender has developed Ni catalyzed intramolecular [4+4] cycloadditions (JACS, 1986,
108, 4678-9) and applied the methodology to a short total synthesis of (+)astericanolide (JACS, 1988, 110, 5906-5908).
Wender also found that alkynones are viable substrates for intramolecular [5+2]
cycloadditions. This reaction was used in the synthesis of the allocyanathin core
(Org. Lett. 2001, 3(13), 2105-2108).
O
O
[Rh(CO)2Cl]2 (5%)
DCE, 80 °C, 3.5h
90%
OH
HO
57%
H
(+)-Allocyathin B2
Mascarenas has discovered a method using chiral sulfoxides to direct the
diastereoselectivity of oxidopyrillium cycloadditions. The diastereoselectivity appears to
result from the rotational preference of the sulfoxide (Org. Lett., 2002, 4(21), 3683-5).
EtO2C
CO2Et
O
O
DBU, PhMe, -30 °C
O
AcO
O
3 h, 86%
1 diastereomer
:
S
H
60 °C, 82%
H
S
:
O
pTol
O pTol
O
Raney Ni, THF
CHO
trans
MeO2C
Ni(COD)2, PPh3
H
O
O
H
O
H
BH3•THF; PCC
H
H
48%
Et
H H
HO
R
Ph
TFA, 50%
Ph O
O
NMe2
HO
Ph
OH
hυ, 0 °C, 100% Et
NH H
Cl2
Fe
R
N
N
.5%
R=
butadiene•Mg•2THF (.7%)
-17 °C, 14 d, 89%, 61 % ee
Ph
Ph
OH
O
Ph
CO2H
Ph
H
O
Darvon
Alcohol
Work on enantioselective intermolecular variations of this reaction has also been done.
Although impressive selectivity in heterodimeriztions has been achieved, albeit in
moderate enantioselectivity (tom Dieck et. al., ACIEE, 1992, 31, 305-6).
CO2Me
MeO2C
O
Ph
O H
N
NaAlH2(OCH2CH2OMe)2
H
H
H H
H H
HO H
HO H
N
O
20%
Ph
Ac
OH
NH
PhH, BF3•OEt2
40-65%
R=Ac, CHO, Me, Et
Ac2O, BF3•OEt2
OH
H O
ROH, H+
RO
The natural product Alteramide A was observed to undergo an intramolecular [4+4]
cycloaddition upon UV irradiation. JOC, 1992, 57(15), 4317-4320.
H
Red-Al
H
(+)-astericanolide
Ph
O
H
H
O
O
Ph
Ph
74%
H
H
[4+4] cycloadditions are photochemically allowed. However, the substrate range is very
limited and the reactions often require harsh conditions (e.g. solid state dimerization of
pyrones, Tet. Lett., 1971, 879-882.
Ph
O
SnMe3
Red-Al, CuBr
H
90 °C, 67%
[4 + 4] Cycloadditions
O
•
O
O
H
O
HO
+
O
N Bn
CO2Me
hυ, solid state
100% brsm
SnMe3
HO
83%
56%
Wender has developed a protocol for hetero [5+2] cycloadditions using cyclopropyl
imines. JACS, 2002, 124, 15154-5.
1. BnNH2
2. [Rh(CO)2Cl]2,
60 °C, PhMe, 82%
Red-Al; Me3SnCl
O
CO2Et
CO2H
2. LDA, -78 to 0°C
69%
OH
1.LiAlH4 93%
HO
2. Swern, 88%
3.Li
88%
4. Swern, 89%
5. LiAlH4, Darvon
97%, 98% ee
BuLi; CO2-
EtO2C
CO2Et
1. isobutyric
anhydride 99%
MgX
CHO
OH
CHO
EtO2C
Group Meeting
8/30/2006
Higher Order Cycloadditions in Synthesis
O'Malley
AcO
-50 to -20 °C
8h, 40%
Ni(II), EtAlCl2, hex
55 °C, 12h, 50%
3
[6 + 2] Cycloadditions
Feldman has studied the photochemical intramolecular cycloadditions of tropones.
(JOC, 1989, 54(3), 592-601). This reaction was applied in a synthesis of (+)-dactylol
(JACS, 1990, 112(23),8490-8496).
O
Wender has extended his Rh-catalyzed methodology to vinyl cyclobutanones (JACS,
2000, 122(32), 7815-6).
R1
OH
hυ, CHCl3, -60 °C
H
*
H
HO
70-90% for X=NTs, O, C(CO2Me)2;
R1,R2= H, Me
OH
1. Acetylation
2. hυ, HMPA, H2O
50%
-10 °C, PhMe, 87%
R2
H
HO
•
O
TsN
H
RO2C
O
hυ
H
CO2Me
N
H
CO2R
N
O
Cr(CO)3
Ph
Rigby has extensively studied both thermal and metal-mediated cycloadditions of a
variety of partners (JACS, 1993, 115(4), 1382-1396).
H
O
MeO2C
MeOH, 85%
MeO
OMe
Me
H
N
H
O
(+)-ferruginine
N
CO2R
H
O
H
15%, >98%de
58%, >98%de
MeO2C
1. LiOH, 84%
N
2.ClCO2iBu, NMM;
H
N-OH-pyr-2-thione;
MeO
tBuSH, hυ, 49%
H
1. TFA, H2O/acetone
2. MeMgBr; LiAlH4;
H
140 °C, 63%
Note: presence of exo
product is very unusual.
H
TsN
[6 + 4] cycloadditions
MeO2C
H
O
H
Rigby has developed Cr(0)-mediated [6+2] and hetero-[6+2] additions using Cr
coordination complexes.This reaction was used to synthesize (+)-ferruginine
(JOC, 1995, 60, 7392-3).
N
H
[Rh(CO)2Cl]2
PhMe, 110 °C
0.75 h, 91%
(+)-dactylol
CO2Me
O
X
2. LiAlH4, 74%
OH
Pd-C, H2
Rh(I), (Ag(OTf))
R1 O
R2
X
1. PhC(Me)2O2Li
O
41%, 11:1 dr
Tl(NO3)3
Group Meeting
8/30/2006
Higher Order Cycloadditions in Synthesis
O'Malley
exo
MeO
OMe 1.
hυ
O
H
DMP, 28%
H
2. P(OMe)3
3. H+, 56%
(OC)3Cr
OMe
endo
Interestingly, the electronic nature of the diene seems to have little effect on the yield of
the metal-mediated reaction. Lewis acids appear to catalyze the thermal cycloaddition
(Tet. Lett. 2002, 43, 8643-6.
O
O
H
FeCl3(0.25 eq), DCM, 4A mol. sieves
48 h, 85%
Ti(OiPr)2Cl2 (0.3 eq), S-BINOL (0.3 eq)
DCM, 4A mol sieves, 36 h, 80%, 40% ee
H
4
Rigby used the cycloaddition of a sulfone in a synthesis of estradiol (JACS, 1999,
121(36), 8237-8245).
1. hυ
H
2. CO, 70%
H
Cr(CO)3
X Rh(acac)(CO)2(1%)
SO2
1.tBuOK, -105 °C
OH
1. KNH(CH2)3NH2 71%
2. HF
3. TESH, TFA, 38%
4. Pb(OTFA)4, 80%
H
H
H
CO, THF, rt
Y
H
H
OTBS
H
O
R
R
H
TMS
2. NCS
3. tBuOK, -105 °C
TMS
60%
Ojima has discovered a method for intramolecular carbonylative [2+2+2+1]
cycloadditions (JACS, 2005, 127(50), 17756-17767.
OTBS
OTBS
O2
S
TMS
Group Meeting
8/30/2006
Higher Order Cycloadditions in Synthesis
O'Malley
H
HO
(+)-estradiol
X
50-90% (usually >80%) for R=H, X,Y=O, NTs, C(CO2Et)2, C(CH2OP)2, C(CH2OH)2
50-100% for R=Me, Ph, TMS (often includes [2+2+2] product)
Rigby has discovered that Cr complexes can participate in [6+2+2] cycloadditions with
alkynes. This process appears to be a [6+2] cycloaddition followed by a [4+2+2]
cycloaddition. This was applied to a synthesis of 9-epi-pentalenic acid. (JOC, 2004, 69,
6751)
OTIPS
Multicomponent Cycloadditions
R
Co(acac)2, R-Prophos
Et2AlCl
R
Prophos=
Ph3P
PPh3
HO
hυ, DCE
TIPSO
70%
Cr(CO)3
Lautens has reported enantioselective [4+2+2] cycloadditions with norbonadiene
(JOC, 1993, 58(17), 4513-5, JACS, 1995, 117(26), 6863-6879).
R=Me, 66%, 72% ee
R=homoprenyl, 49%, 79% ee
R=(CH2)3OAc, 52%, 73% ee
Y
HH
H
H
9
H
H
HO2C
9-epi-pentalenic acid
Wender has extended his vinylcyclopropane methodology to carbonylative [5+2+1]
cycloadditions for the synthesis of bicyclo[3.3.0]octanes (JACS, 2002, 124, 2876-7).
P. A. Evans, has done extensive work on [4+2+2] cycloadditions
(JACS, 2002, 124, 8782-3).
O
TsN
[Rh(PPh3)3Cl] (10%)
butadiene, AgX
PhMe, reflux
TsN
TsN
OCO2Me
[Rh(PPh3)3Cl] (10%)
AgOTf, PhMe, Rt;
heat, 87%
Np
R
PO
E
H+
H
3%
89%
O
Multiple examples: E=COMe, CONH2, CHO, CO2Me, R=alkyl,Ph, TMS (CO2Me works, but gives 48%)
O
Pd(PPh3)4 (5%)
TsN
Np
OH R
Ito has reported a carbonylative [4+4+1] dimerization of ene-allenes (ACIEE, 1998,
37(24), 3418-3420.
TsN
[Rh(PPh3)3Cl] (10%)
butadiene, AgX
PhMe, reflux
91%, dr>19:1
E
E
•
TsN
O
R
X=OTf: 85%
X=SbF6: 2%
Ts(Li)N
NTs
O
H
CO, THF, 40h, 61%