Group Meeting
2/29/2005
Alois Fürstner
O'Malley
Prof. Alois Fürstner was born in 1962 in Bruck an der Mur,
Austria. He received his Ph.D. in 1987 from the Technical
University of Graz under Prof. Weidmann. In 1990-1991, he
was engaged in postdoctoral studies with Prof. Oppolzer at the
University of Geneva. He completed his habilitation in 1992 at
the Technical University of Graz and obtained a position as a
professor at the Max-Planck-Institut für Kohlenforschung. In
1998, he was promoted to director. He is also affiliated with the
University of Dortmund. His contributions to chemistry have
been recognized with numerous awards, including the
Dozentenstipendium of the Fonds der Chemischen Industrie
(1994), the Arthur C. Cope Scholar Award (2002), and the Otto
Bayer Prize (2006).
O
M
O
M
L
B
OR
C
O
Grubbs I (3 mol%)
Ti(OiPr)4 (30%)
O
OTBS
OTBS O
CH2Cl2, 40 °C
80% E:Z 2.7:1
O
KMnO4, Ac2O;
aq. HF, MeCN, 54%
H
The Fürstner group has made impressive contributions in the field of ring-closing alkene metathesis,
particularly the areas of: (i) extension to the synthesis of medium and macrocyclic rings (ii) control of
product stereochemistry (iii) development of new catalyst systems (iv) application to the total synthesis
of complex natural products.
The Fürstner group helped pioneer the use of RCM for the formation of medium and large rings. They
used RCM of a cyclooctene as the key step in their short synthesis of Dactylol. JOC, 1996, 61, 8746-9.
O
OR
L
A
Research in the Fürstner group focuses on organometallic
chemistry and its application to the synthesis of complex natural
products. Specific areas of focus include alkene and alkyne
metathesis, development of new metal catalyzed and mediated
reactions, and the preparation and use of active metals.
Alkene Metathesis
M
O
O
O
H
OH
Cl
O
O
Cl
Grubbs I: R = Ph
Grubbs IA: R= CH=CPh2
PCy3
Ru
PCy3
R
H
(—)-Gleosporone
8 steps, 18%
It was initially believed that macrocylizations using RCM required either a directing group or a
conformational predisposition towards cyclization to succeed. The Fürstner group disproved this in their
synthesis of several natural odoriferous macrolactones. JOC, 1996, 61, 3942-3943.
O
O
TMSO
6 steps
Schrock catalyst (3%),
C6H14, 55 °C; TBAF, 92%
HO
O
X
Y
O
Me H
F3C
CF3
Ph
Gubbs IA (4 mol %);
H2, Pd-C
X=8, Y=4; 79%; 94%
X=3, Y=9; 62%; 95%
O
ExaltolideTM
Dactylol (17% overall)
O
Schrock
Catalyst
Mo
O
N
F3C
F3C
In macrocyclizations where the double bond is to be retained rather than hydrogenated, E/Z selectivity of
RCM can pose a difficult problem. The Fürstner group reported that remote functionality can play a key
role in obtaining selectivity. A hydrogen bond between the unprotected phenol and the ester carbonyl is
believed to be responsible for this selectivity. Org. Lett. 2000, 2, 3731-4.
OR
It was discovered early on that the presence of a "directing" functional group greatly assisted the
formation of macrocycles (see structure A). However, such groups could also result in stable chelates
that sequester the catalyst (B and C). The Fürstner group found that the use of mild Lewis acids such as
Ti(OiPr)4 could overcome such chelation in their synthesis of (—)-Gleosporone. JACS, 1997, 119, 9130-6.
OPMB
OPMB
O
O
OMOM
OR
Grubbs II
O
O
Cl
OMOM
PCy3
Ph
Ru
Cl
Mes N
N Mes
R=H, 10% cat., 20h, 69%, 0:100 E:Z
R=Me, 5%, 1.5 h, 93%, 66:34
R=MOM, 10%, 3h, 91%, 68:32
R=TBS, 5%, 1h, 91%, 40:60
1
Alkene metathesis is an inherintly reversible process. This can particularly pose difficulties for the
synthesis of medium sized cycloalkenes. However, the process can be driven towards ring closure
by evolution of volatile byproduct olefins (e.g. ethlyene) from the reaction medium. Also, when the
product olefin is highly substituted, less active catalysts may be insufficiently reactive to initiate
Ring Opening Metathesis. This reversibility also allows for equibilibration of olefin geometry. The
Fürstner group exploited this phenomenon in their synthesis of the herbrumins, where the Z olefin was
calculated to be 3.5 kcal/mol more stable than the desired E isomer. This is the first example of the
selective synthesis of both isomers of a target by catalyst choice. JACS, 2002, 124, 7061-9.
H
CH2Cl2 reflux
69% + 9% Z
H
H
O
Fürstner cat.
aq. HCl, 90%
O
O
H
H
CrO3, Ac2O
Cat. D (5%), 50 min 37%, 27% trimer,
11 % oligomer; extended time favors
trimer and oligomers
Cat. B (5%) gives 81% trimer
O
aq. HCl, 47%
O
O
Pyrenophorin
4 steps, 12%
O
O
OH
H
O
O
HO
H
O
O
Ph
O
O
BnO
O
O
O
BnO
O
3. TFA, CH2Cl2
4. H2, Pd/C, MeOH, TFA
49%
O
O
Ph
PCy3
O
O
O
O
O
3
Cl
PCy3
PCy3
PCy3
Ph
Cl
Ph
Cl
Mes N
B
2
O
Cl
2,6iPrPh N
Ph
H
O
O
HO
HO
O
Tricolorin G
O
O
O
(tBuO)3W CMe3
5 mol %
O
O
O
Cl
PCy3
Ph
Ru
N 2,6iPrPh
C
O
80 °C, 73%
PCy3
Ru
N Mes
O
In 1998, Fürstner reported the first use of Ring Closing Alkyne Metathesis for the synthesis of
macrocycles with 12 or more atoms in the ring. ACIEE, 1998, 37, 1734-5.
O
Ru
O
Alkyne Metathesis
O
O
O
HO
The first effective catalyst for alkyne cross-metathesis was reported in 1968. However, this heterogenous
mixture of tungsten oxides and silica was only active at temperatures above 200 degrees, and so was not
useful for organic synthesis. In 1974, Mortreux et. al. reported that a mixture of Mo(CO)6 and simple
phenols catalyzed alkyne methathesis at high temperatures (ca. 150 °C). The active species in this
system is unknown, but believed to be a metal carbyne. In 1982, the Schrock group reported the welldefined catalyst (tBuO)3W=CCMe3, which is active at temperatures as low as room temperature.
For a review, see Chem. Comm. 2005, 2307-2320.
O
1
cat.
t(h) prod.
A(10%) 17 2(79%)
B(10%) 40 3(65%)
C(3%)
4 1(25%) 2(29%) 3 (10%)
C(6%) 40 3(57%)
D(6%) 40 3(57%)
exposure of 2 to catalyst C
for 28 h gives 3 (60%)
HO
HO
HO
O
O
The Fürstner group also discovered uses for the reversibility of RCM reactions in the formation of
macrocyclces with trisubstituted olefins and dimeric macrocycles. Org. Lett. 2001, 3, 449-451.
Ru
1. Grubbs Ia
2. H2, RhCl(PPh3)3, 93%
O
O
BnO
Ru
A
O
O
The Fürstner lab has also used RCM as a key step in the synthesis of a number of highly complex
molecules, most notably glycolipids such as Tricolorin G. JACS, 1999, 121, 7814-7821.
HO
Fürstner Catalyst: See Chem.-Eur. J., 2001, 7, 4811, and references therein.
PCy3
Cl
O
O
O
AcOH, PhH,
0 °C 54%
O
H
O
Grubbs II
CH2Cl2 reflux
86%
Cl
O
O
HO
H
O
Cl
O
herbarumin I
O
H
Cl
O
O
HO
O
O
O
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
Cl
Mes N
N Mes
D
2
Alkyne Cross Metathesis has been almost unexplored, but was used in a synthesis of prostaglandins
and prostaglandin analogues. JACS, 2000, 122, 11799-11805.
MeO
O
O
O
TBSO
O
CO2Me
OMe
Catalyst A
51%, balance recovered SM
OTES
TBSO
[Cp*Ru(MeCN)3]PF6
(1 mol%), HSi(OEt)3
Si(OEt)3
X tBu
tBu
Mo
tBu
tBu
84%
90% (91:9 E:Z)
Unsymmetrical alkynes generally give mixtures of regioisomers; E:Z is generally > 98:2.
The enyne-alkyne metathesis was then applied in a synthesis of Lantrunculin A. ACIEE, 2005, 44, 34623466.
tBu
tBu
Mo
tBu
Catalyst A
Potential Active Species
O
O
Note: the exact active species in this reaction are unknown. Multiple Mo complexs have been isolated and
possess varying degrees of reactivity in metathesis reactions. Also note that these Mo catalysts can
activate N2, so reactions must be carried out under Ar.
O
H
Cat. A (10 mol%)
O
H
PhMe/DCM, 80 °C
70%
OMe
S
S
OTBS
N
O
PhMe/DCM, 80 °C
8h, 80%
OTBS
N
O
MeO
O
2. aq. HF, MeCN, 79%
OH
N
HN
S
O
(tBuO)3W
S
1. Lindlar, H2, quant.
OH
O
O
O
OTBS O
O
H
The utility of the product cycloalkynes has been extended beyond semireduction to stereodefined
alkenes. In their synthesis of citreofuran, the Fürstner group used the alkyne as a precursor to a
brideged furan. JOC, 2003, 68, 1521-1528.
O
O
OTBS O
2. TBAF, 62%
3. aq. AcOH, 80%
S
O
Cat. A (10%)
OMe
O
1. Lindlar, H2, 82%
TeocN
TeocN
S
O
O
O
O
AgF or
AgF(cat.)/TBAF
R
tBu
Mo
The synthesis of conjugated dienes has thus far eluded alkene metathesis. In addition to the usual
issues of product geometry, such reactions also face a question of selectivity with regards to which
alkene in the starting diene participates in the reaction. As a result, such reactions often generate
intractable mixtures of geometrical isomers of both the desired and ring-contracted products. Alkyne
metathesis catalysts react with alkynes chemoselectively, thus making enyne-alkyne metathesis an
attractive method for the synthesis of macrocyclic dienes. The Fürstner group reported the use of an
alkyne metathesis-trans hydrosilation/protodesilylation protocol for the selective synthesis of Ecycloalkenes and E,E-cycloalkadienes. Tetrahedron, 2004, 60, 7315-7324.
OTES
The Fürstner group developed a well-defined Molybdenum complex that functions as a highly
effective alkyne metathesis catlyst when activated with a wide variety of haloalkanes (often CH2Cl2)
or TMSCl. This catalyst was then applied to a highly efficient synthesis of epothilones A and C.
The excellent yield obtained in the RCAM reaction contrasts with the poor E/Z selectivities in early
epothilone syntheses which relied on alkene metathesis. Chem. Eur. J. 2001, 5299-5317.
tBu
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
OMe
CMe3
O
MeO
1. TsOH, 85%
O
85 °C, 78%
2. 9-I-BBN, 60%
OMe
O
O
OH
O
O
Epothilone A: 14 steps, 5.1%
from 3-hydroxypropionitrile
O
MeO
O
Best results in previous syntheses used the terminal alkene version of this SM, Grubbs I, 86%, 1.7:1 E:Z.
OMe
Citreofuran
3
Development of Novel Metal Catalyzed and Mediated Reactions
The Fürstner group has developed procedures for the Ti-mediated synthesis of a number of heterocycles.
Tetrahedron 1992, 48, 5991-6010. As background, it is important to note that, although the "McMurry"
reagents formed from a variety of Ti precursors and reducing agents are often thought of simply as "Ti(0)",
there are important differences in the composition and oxidation potentials of these reagents. See
Fürstner,A. "The McMurry Reaction and Related Transformations" in Transition Metals for Organic
Synthesis, 2nd ed. Wiley, 2004, 449-468, for a detailed discussion.
K + 8C(graphite)
150 °C, 10 min
THF reflux
TiCl3 + 3KC8
R
O
O
O
Ti-Graphite
Ideally, commercially avaiable titanium dust would be used as the source of Ti for these reactions.
Unfortunately, the passivating layer of titanium oxides which coat titanium metal has defied all attempts at
activation. However, the successful development of the catalytic protocol led to the discovery that TMSCl
could be used as an activating agent.
Ph
N
H
Titanium on graphite
R
O
Ph
O
R
Ti (65 eq.)
TMSCl (65 eq.)
preactivate 68 h
Ph
R
N
H
Ti-Graphite
R
O
R
"Instant" low-valent Ti conditions involving the reduction of complexed Ti salts with Zn in situ were also
found to give excellent selectivity in this transformation. JOC, 1994, 5215-5229.
O
TiCl3, Zn, THF
N
H
N
N
O
Depending on the nature of the substrate and transformation, low-valent Ti mediated reactions often
require several equivalents of Ti salts, this can be inconvenient particularly on large scale or when highly
reactive reducing agents e.g. K or LiAlH4 are used. A procedure for the use of catalytic Ti is highly
desirable, but the strength of Ti-O bonds generally procludes the reduction of the titanium oxides formed
in this reaction. Using chlorosilanes and stoichiometric Zn, the Fürstner group has developed a procedure
for McMurray reactions catalytic in TiCl3. JACS, 1995, 117, 4468-4475.
Cl
TiCl3 (10 mol%)
Zn (5 eq.), TMSCl (5 eq.)
Ph
O
N
H
OEt
O
MeCN reflux, 30 min
73%
OMe p-MeO-C H OCH Br
6 4
2
Ti-graphite
DME reflux, 52%
N
H
K2CO3, 91%
O
O
N
H
O
O
Ar
HO
1. tBuOK; Ac2O,
NaOAc, reflux 59%
2. BBr3, -78 0 °C
Ph
Cl
OMe
N
Ar = p-OMeC6H4
complete retention of chirality
O
Ar
Ar
OMe
CF3
CF3
Ar
Ar
Ar
O
NH
O
O
The coupling of an amide and a ketone to form a pyrrole was used as the centerpiece of an expedient
synthesis of Lukianol A. JOC, 1995, 60, 6637-6641.
Ar
Ph
reflux, 90%
N
H
Ph
Ph
R
Ph
O
Ph
(CH2)26
DME (0.02 M) reflux 6h, 90%
(CH2)26
H
N
Ph
DME reflux, 92%
Ph
R
and
R
H
N
The use of commercial Ti powder was found to be particularly advantageous for macrocyclizations; a 36
membered ring could be formed in excellent yield without the normal precautions (extremely high dilution,
slow addition of substrate).
O
Ph
R
O
O
Ti dust (3 eq),
TMSCl (3 eq.)
O
O
KC8 (potassium-graphite laminate)
R
R
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
OH
O
N
O
OEt
O
OH
Lukianol A
8 steps, 12%
4
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
Ti mediated indole synthesis was the key step in the recently reported synthesis of Dictyodendrin B.
JACS, 2005, 127, 11620-11621.
MeO
O
NO2
O
1. iPrBr, K2CO3,
OiPr
MeO
NO2
-30 °C;
pMBCH2Br, 83%
2. Fe, HCl, 96%
2. pMBCHO,
NaOMe, 70 °C MeO
74%
TPAP (10%), NMO
NH2
O
OiPr
OMe
O
66%
N
N
R
R=CH2CH2C6H4OMe
OMe
MeO
DMAP, NEt3
TiCl3/2 KC8
O
O
HN
Cl
OH
N
OH
OH
OMe
Dictyodendrin B
13 steps, 8%
OMe
DME/py reflux
71-93%
O
N
R
OiPr
OMe
1. BCl3, TBAI,
-20 °C, 85%
O
2. Cl3CCH2OSO2Cl,
DABCO, 92%
3. BCl3, TBAI,
0 °C to rt;
Zn,HCO2NH4,
HO
58%
NH
MeO
OMe
OMe
MeO
OiPr
MeO
89%
NH
NH
OiPr1.TosMIC, NaH
OH 99%
OSO3Na
HO
N
OMe
R
OiPr
MeO
hu, Pd/C, PhNO2
81%
OiPr
MeO
NH
NH
OMe
OMe
HO
2. MeLi; BuLi; pMBCHO
-78 °C to rt, 97%
R
OMe
OH
I
1. NBS, 0 °C, 69%
N
The Nozaki-Hiyama-Kishi coupling is the addition of organochromium(III) reagents to electrophiles,
usually aldehydes. The organochroumium reagents are generally derived from the Ni or Pd catalyzed
reduction of active (allyl, alkenyl, aryl, etc.) halides with Cr(II). The excellent selectivity and functional
group tolerance of this reaction has caused it to become the coupling method of choice for the synthesis
of many complex natural products, most notably Kishi's synthesis of Palytoxin. However, there are a
number drawbacks. The Cr(II) salts, which must often be used in significant excess are highly toxic.
Moreover, the requirement to use excess chromium is prohibitive to efforts to find an enantioselective
version of this reaction. While the strength of the Cr-O bond formed in the product gives this reaction a
powerful thermodynamic driving force, it also complicates the task of liberating the Cr to react further.
Drawing on their experience with developing catalytic Ti carbonyl couplings, the Fürstner group
developed the first Nozaki-Hiyama-Kishi coupling reaction using catalytic Cr(II). Zn proved to be
unsuitable due to the sensitivity of many aldehydes to the Lewis acidic ZnX2 generated by the reduction
of Cr(III). Mn proved to be a suitable substitute, and the Cr(II)/Mn/TMSCl conditions have provided the
basis for several subsequent asymmetric variants of this reaction. JACS,1996, 118, 2533-2534, 1234912357.
MeO
O
+
H
N
R
OMe
400 mol %CrCl2, 20 °C, DMF, 78%
15 mol% CrCl2,1.7 eq Mn, 2.4 eq. TMSCl 50 °C, DMF/DME, 67%
15 mol% CrCl2,1.7 eq Mn, 2.4 eq. ClMe2Si(CH2)3CN 50 °C, DMF/DME, 72%
CrCl2 is doped with NiCl2 (ca. 15%)
5
Organomanganese reagents have received increased attention lately as alternatives to organolithiums,
organocuprates, and Grignard reagents due to their improved selectivity, functional group
tolerance, and ease of handling. (For a discussion, see Cahiez, G. and Mahueau-Betzer, F.
"Manganese Organometallics for the Chemoselective Synthesis of Polyfunctional Compounds", in
Handbook of Functionalized Organometallics, Wiley, 2005, 541-568). However, their utility has been
limited by the traditional method of their synthesis: transmetallation from an organolithium or Grignard.
Direct oxidative insertion of Mn(0) is an attractive proposition, as it would allow the use of
organomanganese reagents containing functional groups incompatible with less selective organometallics.
However, the passive oxide coating on commercial Mn(0) prevents such reactivity. The Fürstner group has
reported one solution to this problem by using potassium-graphite laminate. Tet. Lett. 1996, 37, 7009-7012.
2 KC8
MnBr2•LiBr
THF, -20 °C, 1h
O
Cl
O
Fe(acac)3 (3 mol%)
C6H13
MeMgBr (1.3 eq)
85%
Br
Ph
NCO
O
MnC8
Me
Br
NCO
NC
F
Palladium catalyzed cross couplings form an indispensable part of a synthetic chemist's repertoire.
However, these reactions have a number of drawbacks, particularly on large scale:
1. palladium catalysts are expensive and toxic; specialized ligands can add to this cost
2. most systems require expensive aryl or akenyl iodides, bromides, or triflates; only recently have
specialized systems for chlorides been found and tosylates have largely been ignored
3. ß-hydride elimination restricts the use of akyl partners to specialized systems or prevents it entirely
The Fürstner group has developed protocols for Fe catalyzed couplings of Grignards and halides and
pseudohalides that function as an attractive complement to or even substitute for Pd catalyzed couplings.
Interestingly, aryl chlorides, triflates, and tosylates react much more readily with alkyl Grignards than iodides
and bromides. These reactions proceed in under 5 min., allowing the use of functional groups normally
incompatible with Grignards, such as ketones and esters. ACIEE, 2002, 41, 609-612, JOC, 2004, 69,
3943-3949, JACS, 2002, 124, 13856-13863.
O
OMe
Ph
Ph
THF, -20 °C
91%
Two anomolous, though interesting cases were reported.
O
O
O
1 (5%) PhMgBr
I
THF, 0 °C
85%
O
1 (5%) PhMgBr
I
THF, 0 °C
77%
O
O
Ph
O
O
The Fe catalyzed coupling reaction has also been extended to propargyl epoxides, which form allenyl
alcohols with nearly complete retention of chirality. The syn adducts are highly favored, complementing
previous organocuprate methodologies, which favor anti products. ACIEE, 2003, 42, 5355-5357. This
coupling was used in an elegant synthesis of amphidinolide X. JACS, 2004, 126, 15970-15971.
1. Swern
TBDPSO
2. (MeO)2P(O)C(N2)COMe, 67%
Ti(OiPr)4, (+)-DET TBDPSO
OH
C6H13
X %yield(GC)
I 27(46% X=H)
Br 38(50% X=H)
Cl
>95
OTf >95
OTs >95
[Li(tmeda)2][Fe(C2H4)4] (1)
O
1 (5%) PhMgBr
Ph
I
F
THF/NMP,
0 °C to rt, 5 min
Fe(acac)3 (3 mol%)
Alkyl halides and aryl Grignards also couple efficiently using a different Fe catalyst. ACIEE, 2004, 43,
3955-3957.
O
n-hexylMgBr
Fe(acac)3 (5 mol%)
O
Cl
n-hexylMgBr (1.3 eq)
90%
I
O
NC
X
O
THF, -20 °C
90%
Cl
OMe
Acid chlorides are also active partners. No problems with addition to the product ketones were seen,
particularly when the acid chloride was added to the Grignard solution.
1 (5%) PhMgBr
Mn-graphite + n LiBr + 2 KBr
I
O
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
TBDPSO
O
O
tBuOOH, 97%
83% ee
PrMgCl, Fe(acac)3
TBDPSO
OH
3. LHMDS, MeOTF, 95%
AgNO3, CaCO3
•
62%, syn:anti 8:1
90%
In this system, alkenyl, aryl, and allyl Grignards gave poor results, perhaps due to oxidative dimerization.
O
OTf
Fe(acac)3, MeMgBr O
-30 °C, 73%
Me
TBDPSO
TBDPSO
O
1. NBS, DMF,
H2O, 65%
2. AIBN, TTMS
O
HCO2
1. NaHCO3, MeOH, I
90%
2. PMBOC(NH)CCl3
O
PPTS, 76%
PMBO
3. TBAF, 97%
4. I2, PPh3 92%
6
O
O
1. Et2Zn, Pd(OAc)2
+
O
O
OPMB
O
Cp2ZrHCl; I2
PPh3, 65%
anti:syn 4.5:1
2. PMBCl, NaH
TBAI, 94%
3. LHMDS, MeI, 95%
OMs
O
O
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
OH
In their synthes of Cycloviracin B1, the Fürstner group used an elegant potassium-templated
cyclodimerization to form the core macrocycle. The use of other cations led to greatly reduced yields.
JACS, 2002, 124, 1168-1169, 10274-10275.
OBn
61%
TBDPSO(H2C)13 BnO
O
OH
O
I
O
(EtO)2
O
P
OMe
TIPSO
OMe
TIPSO
N
Cl
OH
K
DMAP. KH, 71%
O
HO
O
O
BnO
isoprene, 92%
LiCl, DBU, 94%
N
O
OH
1. HF, py, 100%
2. Swern
3. NaClO2, NaH2PO4
O
Cl
OBn
OBn (CH2)13OTBDPS
OBn
O
OBn
O
O
OH
TBDPSO(H2C)13 BnO
O
OMe
HO
O
O
OMe
O
I
2,4,6-ClPhCOCl,
DMAP, NEt3, 96%
O
OBn
O
I
O
O
O
O
O
O
O
+
BnO
I
O
B
tBuLi; 9-OMe-BBN
OMe
Li
PMBO
O
O
OBn (CH2)13OTBDPS
OBn
O
PMBO
OMe
1. (dppf)PdCl2, Ph3As, 74%
2. LiI, py, 125 °C
3. aq. AcOH, 53%
4. DDQ, 84%
O
HO
O
O
O
O
O
O
2,4,6-ClPhCOCl,
DMAP, NEt3, 62%
O
O
O
O
HO
O
OH
HO
HO
O
HO
OH
O
O
O
CO2H
O
HO
HO
OH
O
O
OH
O
O
OMe
OH
O
O
OMe
OH
O
OH
OH
OH
OH
Cycloviracin B1
7
Group Meeting
2/29/2005
Alois Fürstner
O'Malley
The Fürstner group has synthesized several natural products in the roseophilin family (for a review, see
ACIEE, 2003, 42, 3582-3603). Particularly notable is their synthesis of Streptorubin B and
Metacycloprodigiosin (JACS, 1998, 120, 8305-8314). This synthesis featured a Pt catalyzed cyclization
of an enyne, which has led to the development of a variety of related methods (see ChemtractsOrganic Chemistry, 2003, 16, 397-425).
Ts
N
NaH;
TsHN
Se, Chloramine T
Late addition: As a testament to the effectiveness of the Fe catalyzed coupling reaction, Isobe used this
procedure in a synthesis of the HIJKLM ring fragment of Ciguatoxin. Org. Lett. ASAP.
O
H
Br
O
; 92%
O
TBSO
Ts
Ts
N
N
1. Bu3SnH, Pd(0)
HBF4, 94%
2. LiAlH4, 96%
3. PhOC(S)Cl, 95%
4. Bu3SnH, AIBN 64%
PtCl2 (5 mol%)
1. BuLi, -78 °C
2. ZnCl2, -30 °C
3. butanoyl chloride O
82%
rt, 66h, 79%
MeO
+
H
O
O
OTBS
H
O
THF/NMP, 89%
OTIPS
H
O O
H
H
Ph
1.KHMDS, PhNTF2
2.Fe(acac)3, MeMgBr
H
H
O
O H
H
O
TBSO
HN
O H
H
O
O
OTIPS
H
O O
H
H
Ph
75%
O
H
O
H
OTBS
H
CHO
NH
NH
Known Procedure
NH
N
MeO
H
N
streptorubin B
8