Cyclopropanes in Synthesis
Wednesday, February 18, 2004
J. Gallagher
Walsh Oribital Energies
An Brief History of Cyclopropanes-
H H
1884 First synthesis of a cyclopropane derivative by William Henry Perkin with Adolf von Baeyer's.
1896 Vinylcyclopropane synthesized by Gustavson.
1922 Existence of vinylcyclopropane secured, yet faces despite residual disbelief.
1931 Pauling describes the banana bonding model of cyclopropane
1942 Cyclopropanol synthesize by Cottle.
1947 Walsh describes cyclopropane as a coordinate bond between ethylene and :CH2
1952 Hexafluorocyclopropane generated by TFE photolysis.
1954 Doering et al. find dichlorocarbene adds into alkenes to generate gemdichlorocyclopropane.
1957 Triphenyl cyclopropenylium perchlorate synthesized byr Breslow, constituting the smallest
aromatic species possible.
1958 Simmons and Smith determine that iodoalkylzinc species are capable of cyclopropanation.
1964 Wittig elaborates diazoalkanes as an alternative to iodoalkane precursors oforganozinc
species.
H H
6.8 eV
H
H
H
E
H
H
H
H
H
-3.4 eV
H H
H
H
H
H
H
H
H
H
H H
H H
H
H
H
-13.2 eV
H
H
H
H
-15.4 eV
H H
Physical Descriptions of Cyclopropane-Pauling's sp3, "banana" bonded cyclopropane: This model suggests that sp3 hybridized carbons
give rise to a stable, trigonal planar arrangement. Further instability is inferred as all hydrogens are
eclipsed.
H
H
H
H
H
H
H
H
CH2
H
H
H
H
H
H
Used with permission from Daniel J.
Berger
Outline of Cyclopropanes in Synthesis:
-Walsh cyclopropane description: In an analogy to epoxides, A.D. Walsh proposed that
cyclopropanes be considered as an insertion of methylene into ethylene, ultimately giving rise to the
D3h symmetric product.
H
H
HH
HH
Thus, Walsh cyclopropane has significant sp2 character and should react in analogy to olefins;
further, as reactivity is generally governed by HOMO-LUMO chemistry, one can also see why Walsh
cyclopropane has a propensity to open, yet while it is also a stable compound. The dative bond
suggestion was immediately hated by the British chemical community, with Sir. R. Robinson leading
the criticism. Walsh's suggestions had been picked apart due to his suggestion of subtle similiarities
between ethylene oxide/cyclopropane and N-oxide species, ethylene, and the relationship between
chemical character and depiction. Experimental support, however, was presented a year later for
cyclopropane's olefinic character, strengthening Walsh's hypothesis.
H
- Stereocontrol via cyclopropanation:
• Corey's syntheses of (±)-Atractyligenin and (±)-Cafestol
• Smith's synthesis of (±)-MycorrhizinA and (±)-Dechloromychorrhizin A
- Cyclopropanes as equivalents or masked groups:
• Danishefsky's synthesis of Epothilone A
• Carreira's synthesis of (–)-Spirotryptostatin and (±)-Horsfilin
- Synthesis of unusual cyclopropanated natural products:
• Barrett's synthesis of FR-900848
• Falck's synthesis of FR-900848
Cyclopropanes in Synthesis
J. Gallagher
Epothilone A: Danishefsky et al., JACS, 1997, 10073
Cyclopropanes in Selected Total Syntheses:
O
S
H
N
H
O
O
H
O
H
O
OH
, PPTS,
CH2Cl2, r.t., 73% THPO
O
HO
N
N
NMe
O
MeO
H
OH
N
H
OH
O
(-)-Spirotryptostatin B
Epothilone A
O
N
H
S
S
N
N
(±)-Horsfiline
H
OR 1) NIS, AgNO
3
OH
OH
Me
HO
OH
O
H
MeO2C
(±)-Cafestol
H
H
(±)-Atractyligenin
O
Me
I
O
OH
SiMe3
MOMO H
THF, –78˚C-r.t.
97%
O
O
Cl
Cl O
OMOM
1) PhSH, BF3•Et2O, CH2Cl2, r.t.
2) Ac2O, pyr., 4-DMAP, CH2Cl2, r.t.
86%; 99%
A: R=MOM
B: R=Ac
(-)-Dechloromycorrhizin
O
Me
H
Acetone, 64%
2) (Chx)2BH, Et2O,
AcOH, 65% Me Si
3
O
Me
1) TMS
Li
SiMe3
BF3•Et2O, THF MOMO H
O
–78˚C, 76%
HO
2) MOMCl, iPr2NEt,
(ClCH2)2, 55˚C, 85%
1) (COCl)2, DMSO,
3) PPTS
CH2Cl2, –78˚C; Et3N,
MeOH, 95%
–78˚C-r.t.
2) MeMgBr, Et2O, 0˚C-r.t.
S
O
85% for 2 steps
P Ph
N
3) TPAP, NMO, 4 Å M.S.
Ph
CH2Cl2, 0˚C-r.t.
nBuLi, THF, -78˚C
OMe
NH
H
N
O
OH
(-)-Mycorrhizin
N
O
O
BnO
CHO
1) TiCl4, CH2Cl2, –78˚C
2) CSA, PhH
87%
+
OTMS
O
OH
LAH,
Et2O, –78˚C
91%
O
OBn O
OBn O
OH
OH
Et2Zn, CH2I2,
Et2O, r.t., 93%
FR-900848
OMe
OMe
OBn O
OH
Bu3SnH, AIBN(cat),
OBn O
PhH, ∆
80% for 2 steps
H
I
OH
NIS, MeOH OBn O
r.t.
TPSCl, imid.
DMF, r.t., 97%
OMe
OBn O
1) 1,3, propane dithiol, TiCl4
CH2Cl2, –78˚C-–40˚C
78%
BnO
OTPS 2) TBSOTf, 2,6-Lutidine ,
CH2Cl2, 98%
TBSO
OTPS
S
S
OH
Cyclopropanes in Synthesis
1) DDQ, CH2Cl2/ H2O, 89%
2) (COCl)2, DMSO, CH2Cl2,
–78˚C; Et3N, –78-0˚C, 90%
OBn OTBS OTPS
S
TBSO
S
S
TBSO
S
Rh2(OAc)4, (1mol%)
S
N
N
N
H
S
H
O
O
H
O
OH
OMe
OMe
O
N
N
H
H
H
H
O
Epothilone A
OH
1) DMP,
CH2Cl2, r.t., 84%
2) HF•Pyr.,
THF, r.t., 99%
3) 3,3 DMDO,
CH2Cl2,-35˚C, 49%
16:1 d.e.
S
O
NBOC
H
H
N
H
99%
O
N
H
CO2Me
O
N
N
H
CO2Me
O
NBOC
1) NMO•H2O, OsO4 (cat) H
O
CO2Me THF/tBuOH/H2O, r.t.
N
2) Pb(OAc)4,
EtOAc, r.t., 77%
O
O
N
O
N
NBOC
H
H
LHMDS,
THF, -78˚C
78%
OH
PhSeCl,
LHMDS,
THF, 0˚C
74%
TBAF,
CO2Me THF, r.t.
O
N N
CO2Me
H
H2, Pd/ BaSO4, quinoline,
EtOH, r.t., 90%
O
N
H
N
Ph
N O
NBOC
O
N
N
H
O
N
OTBS
OH
H
O
NBOC
O
O
N
H
NBOC
N
O
OTBS
OTBS
H
O
N
H
1) NaClO2, 2-methyl-2-butene,
O H
tBuOH, pH 3.6, r.t.
TIPS
O 2) CH2N2, Et2O, r.t., 89%
N
H
O
Et3N, NBOC-Pro-Cl
CH2Cl2, r.t., 90%
O
Me
TIPS
S
1) HF•Pyr.,
THF, Pyr., r.t. 99%
2) TBSOTf, 2,6-lutidine
OTPS
CH2Cl2, -30˚C, 93%
O
Me
NBOC
H
OTPS
OTBS
OH
H
O
Resolution of
diastereomers
O
1) NMO•H2O, OsO4 (cat)
THF/tBuOH/H2O, r.t.
2) Pb(OAc)4,
EtOAc, r.t., 97%
TIPS
O
S
Pd(PPh3)4, 6 mol%
1,3-dimethylbarbituric acid
CH2Cl2, 30˚C
Separate isomers
N
TIPS
O
N
H
(sealed tube), 68%
NBOC
Me
N
H
OMe
OMe
KHMDS,
THF, -78˚C, 0.001M
51%, 6:1 d.e.
1) Dess Martin Periodinane (DMP),
CH2Cl2, r.t.
2) NaBH4,
MeOH, THF, -78˚C, 80%overall
H
O THF, 75˚C
N
H
H
N
TIPS
O
O
OTPS
N
PhH, ∆, 71%
O
pTsOH,
Diox./H2O, 50˚C
85%
OTBS
S
O
N
TIPS
TIPS
NBOC
S
O
MgI2,
N
Me
OTPS
OTBS
H
Me
N2
N
1) 9-BBN, THF, r.t.
2) "B", PdCl2(dppf)2,
Cs2CO3, Ph3As,
H2O/DMF, r.t., 75%
OMe
OMe
S
MeOCH2PPh3Cl
tBuOK, THF, 0˚C-r.t.
86%
OTPS
H
OTPS
Me
S
S
PIFA, MeOH, THF, r.t.
92%
TBSO
(-)-Spirotryptostatin B, Carriera et al., ACIEE, 2003, 42, 694
OTPS
OHC
1) pTsOH,
Diox./H2O, 50˚C, 99%
MeO
2) CH3PPh3Br, NaHMDS,
PhCH3, 0˚C-r.t, 76%
OTPS
S
TBSO
J. Gallagher
1) TFA, CH2Cl2,
2) Et3N, CH2Cl2, r.t.
74%
N
H
H
O
H
N
N
N
H
O
O
(-)–Spirotryptostatin B
O
CO2Me
O
Cyclopropanes in Synthesis
Horsfiline, Carriera et al., HCA 2000, 1175
O
MeO
N
H
O
NaH, BnBr
O DMF, 23˚C
74%
N2H4•H2O, ∆
O
91%
N
Bn
Me
O
N
Bn
O
1,2-Dibromoethane, NaH
DMF, 23˚C, 81%
NMe
MeO
NMe
Na/NH3 MeO
O -78˚C, 91%
N
H
(±)-Horsfiline
O
O
O
LDA, MeI
-50˚C-0˚C,
0˚C-5˚C, 70%
O
O
O
N
Bn
O
CO2Me
O
LDA, THF, -60˚C;
-60˚C-0˚C, 67%
N
N
Me
O
Me
O
N
Me
O
Cu(II)(L)2
O
PhCH3, 45-50%
TsN3, DBU
CH2Cl2, 23˚C
98%
O
N2
CO2tBu
O
L:
CO2tBu
NtBu
H
NaBH4,
MeOH, 100%
O
O
OH
H
Me
OH
OH
PPh3, imid., I2
Et2O/ CH3CN
25˚C
MeO2C
Me
Me
CO2Me LDA, HMPA
I
-78C; -78˚C- -20˚C
82%
CO2Et
THF, -78˚C, 86%
4)Rh2(OAc)4
DME, 25˚C, 72%
CH2OH
CO2Et
Me
Me
O
CO2Et
OH
Me
Li
THF/NH3/SiaOH
-45˚C, 89%
Me
2
1) TsN3
Et3N/EtOH,
25˚C, 96%
2) Cu(II)L2
PhCH3,
∆, 67%
H
OH
(±)-Cafestol
LAH, Et2O,
97%
1) DiBAlH,
CH2Cl2, -78˚C, 90%
2) (COCl)2, DMSO
Et3N, CH2Cl2, 95%
3) LDA N
O
tBuO2C
O
OH
H
23˚C
3) CH2C(OLi)(OtBu)
THF, -78˚C, 83%
Me
H
Me
Na
NH3/THF/H2O
-78˚C, 90%
>95:5 d.s. O
1) OsO4, THF
2) H2, Rh-Al2O3
THF, 23˚C
3) HF, THF/
CH3CN, O
23˚C, 55%
Atractyligenin, Corey et al., JACS, 1987, 6187
1) 3% NaOH
THF/ H2O/ MeOH, 23˚C
2)
O
N
H
OH
H
TIPS
H
O
1) NaBH4, MeOH, 0˚C
2) PPh3, imid., I2, 23˚C
84%
O
O
O
Me
Me
H
I
CO2Me
H
OBn
Li,
NH3/THF/EtOH
-78˚C, 100%
tBuLi, THF, -40˚C;
TiPSOTf, 90%
Me
1) Sia2BH, 0˚C, THF
2) 3% H2O2, K2CO3, 63%
Me
H
N2H4, DME/tBuOH, 23˚C;
O2,CH2Cl2, 70%
1) TMS
Li
-35˚C-0˚C
2) PPTS, MgSO4,
O PhH, ∆
3) KF•H2O,
DMSO, 15˚C, 83% O
O
Cl
TFAA, 2,6-lutidine
H CH2Cl2, -78˚C
BnO
O
68%
1) MsCl, Et3N
THF, -50˚C
2) ZnI2,
CH2Cl2, 23˚C
O
72%
Me
83%
Cafestol, Corey et al., JACS, 1987, 4717
Me
Me
1) NaH, BnBr
DMF, 0˚C-23˚C
2) DiBAl-H,
H
CH2Cl2, -10˚C,O
HO
86%
I
N N MgI
2 (cat),
N , THF, 125˚C MeO
O
N
Bn
HOCH2
tBuO2C
MeO
MeO
J. Gallagher
1) Na/Hg, THF/H2O
20˚C
2) CrO3,pyridine
20˚C
3) TFAA, 4-DMAP
pyr./CH2Cl2, 0˚C
4) Zn(s) THF/HOAc
20˚C, 81%!
TBSCl, imid.,
DMF, 20˚C, 91%
Me
LAH,
Et2O, -20˚C
86%
HO
TBSO
Me
O O
CH2OTBS
Me
H
TFAA, Et3N
2,6-ditBu-4Me-pyr.,
69%
O2, Rose Bengal, hu
CH2Cl2/ MeOH, 79%
Me
HO
H
OTBS
Cyclopropanes in Synthesis
J. Gallagher
Mycorrhizin, Dechloromycorrhizin, Smith et al., JACS, 1982, 2659
OTBS
L-Selectride,
THF, -78˚C HO
Me
O
OTBS
Me
O
H
O
1) TBAF
THF, 20˚C
O
2) CPh3OOH
VO(AcAc)2 O
2,6-lutidine
1) 5% Pd-C/ H2 PhH/PhCH3
96%
EtOAc, 20˚C
2) PPh3, CBr4,
CH3CN
3) Zn/AcOH
THF, 65%
O
Me
H
O
MeO2C
H
1) MsCl, Et3N O
CH2Cl2, 0˚C
40%
O
2) LiOtBu
tB uOH/ THF,
m-CPBA
25˚C
CH3OH, 0˚C
O
OMe
CH2OH
1) Li
NH3, tBuOH
2) H2O, (CO2H)2
CH2Cl2
O
H
O
TESCl, Et3N,
DMAP, CH2Cl,
25˚C, 60%
O
OMe
CH2OH
O
OMe
BH3, THF;
H2O2, NaOH
or (+)IPC2BH
60% e.e.
75%
O
LDA,PhSeBr
CH2Cl2, 25˚C
MeO2C
H
1) PCC, 88%
2) SmI2,
THF/ H2O
20˚C, 90%
Me
O
O
Me
H
HBF4(aq)
Dioxane
12.6%
1) Swern
2) SeO2,pyr.,
tBuOH Me
O
OMe
O
O
OH
O
OMe
TBAF
OH
MeO2C
H
H
(±)-atracyligenin
O
OMe
OTES
O
OH
O
O
1) TBAF
THF, 0˚C
2)
Me
Me
LiCu
TMS
TMS
O
OMe
Cl
Cl O
+
2) KF,
DMSO,
25˚C, 60%
O
Me
OH
1) (COCl)2, DMSO, Et3N
65%
Me
O
2) SeO2,
OH
tBuOH, pyr., ∆
O
TMS
1) Cl2
-75˚C
2
75%
O
OMe
OTES
Me
O
Me
2
O
(±)-Dechloromycorrhizin
HO
O
OMe
OTES
O
OMe
OTES
O
OTBS
O
LiCu
H
Me
O
O
O
OH
Me
LiSPr
HMPA
0˚C; 20˚C
84%
MeI, K2CO3
Acetone, ∆
58% overall
OH
TBAF
THF, 20˚C, 97%
H
OMe
O
PPh3=CH2
THF, 25˚C
O
Me
HO
OH
OH
OH
1) Br2
CH2Cl2, 0˚C
2) AlCl3
CH3Cl, 25˚C
O
MeO2C
Me
OMe O
O
O
HO
O
H
1) TBSOTf, 2,6-lutidine
O
CH2Cl2, -78˚C
OH 2) K2CO3,
MeOH, 20˚C, 95%
H
Me
1) nBuLi
Et2O, 34˚C
2) Isobutyryl-Cl
OMe
EtO, -78˚C
78%
1) COCl2
Et3N, THF;
PhSeH;
pyr., PhH
80%
OTBS
2) BuSnH, AIBN,
PhH, ∆, 73%
OH
Me
OMe
O
OH
(±)-Mycorrhizin
1), 2)
3) 50% HBF4, Dioxane
36%
O
Me
TMS
O
O
OMe
Cyclopropanes in Synthesis
FR-900848, Falck et al. JACS 1996, 6096
1) (S,S)-Dioxaborolane,
ZnEt2, CH2I2,
Bu3Sn
OH
CH2Cl2, 23˚C, 98%
2) TPSCl, imid.
DMF, 23˚C, 88%
Bu3Sn
1) s-BuLi
OH THF, -40˚C
*
2) [ICuPBu3]4, TBSO
2
1) TBAF
-78˚C
THF, 23˚C, 72%
3) O2, -78˚C, 73%
2) RuCl3/ NaIO4,
CCl4/CH3CN/H2O,
1) 2-Mercaptopyridine N-oxide,
23˚C, 91%
OH
DCC, DMAP,
Br
TBSO
BrCCl3, 23˚C;
O
2) hu, 77%
TBSO
1) tBuLi,
THF, -78˚C
2) [ICuPBu3]4
-78˚C
3) O2, -78˚C
75%
FR-900848, Barrett et al., CC, 1997, 1693
Borolane 1, ZnEt2,
OH CH2I2, CH2Cl2,
HO
0˚C-25˚C, 89% HO
R'=R:TBS
R:H
R':TBS
HO
NaH, TBSCl
THF, 44%
SO2Ph
O
O
NH
H2N
N
O
O
"B"
O
8.7:
CO2Et 1
+
EtO2C
O
N
O
NaH,
THF, 0-25˚C, 71%
N
NH
O
O
(op. cit.), 51%
4
+
O
O
4
1) H+
2) Rh/C, H2
85%
SO2Ph
BuLi
TMSCl
83%
CO2Me
4
CO2H
O
NH
"B"
H2N
N
O
OH
1) PhSH, PMe3/ADDP
OH
2) AcOOH, 87%
CO2Me
KOSiMe3,
CH2Cl2,85%
N
4
OH
O
1) H+,
O Acetone H2N
2) HN3,
ADDP/PMe3
85%
OTBS
HO
1) PCC, NaOAc, SiO2
CH2Cl2,0-25˚C
2) Z-phosphonate
op. cit., 63%
O
OH
NH
O
4
4
O
4
1) DIBALH
CH2Cl2, -78˚C, 91%
2) Borolane1, op. cit. ,
-40˚C, 90%
OTBS PBu3, PhH, 89%
PhS
TMS
BOP-Cl, Et3N, DMA
69%
O
O
H
N
OH
SO2Ph "A"
NH
N
O
O
FR-900848
OTBS
MeO2C
SPh
N
OTBS
4
(1:5.0) +
MeO2C
O
FR-900848
P(O)(OMe)2
MeO2C
1) Raney Ni,
EtOH, -40˚C
2) NH4F, EtOH, 65˚C
49%
NH
OH
(op. cit.)
63%
H
OH
H
N
2)
O
LHMDS,
THF, -78˚C-23˚C, 89%
2) LiOH,
MeOH/H2O, 23˚C, 90+%
3) DCC, DMAP, Nitrophenol
CH2Cl2, 23˚C, 73% O
DMF, 23˚C
76%
OH
CO2Et
OTBS CH2Cl2, 0-25˚C
1) Li,C10H8, THF
-78˚C, 70%
2) TBAF, THF, 95%
3) TPAP, NMO
O PhpNO2
4
OH
1) PCC, NaOAc, SiO2,
CH2Cl2, 0-25˚C
2) Ph3P=CHCO2Et
CH2Cl2, 67%
PhSH, BuLi, Ti(OiPr)4
THF, 0-25˚C, 50%
OTBS
OEt
O
O
1) DIBALH
CH2Cl2
OH -78˚C, 94%
EtO2C
2) Borolane 1
Et2Zn, CH2I2
DME, -15-25˚C
93%
HO
See step 3
1) (EtO)2P
HO
OH
1) PCC, NaOAc, SiO2
1) TPAP, NMO, 4 Å M.S.
CH2Cl2, 23˚C, 91%
OR'
2) "A", n-BuLi,
THF, -78˚C, 65%
RO
OH
J. Gallagher
OH
OH
O