cis-3,4-dichlorocyclobutene as a versatile synthon in organic synthesis. Rapid entry into complex polycyclic systems with remarkably stereospecific reactions

Article abstract of DOI:10.1002/1521-3773(20011203)40:23<4441::AID-ANIE4441>3.0.CO;2-I

An efficient synthesis of cyclic polyether structures (e.g. 1), which are commonly found in natural products, can be realized from cis-3,4-dichlorocyclobutadiene (2). The versatility of synthon 2 and a mechanistic rationale for the regio- and stereospecif

Full text of DOI:10.1002/1521-3773(20011203)40:23<4441::AID-ANIE4441>3.0.CO;2-I

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cis-3,4-Dichlorocyclobutene (4, Scheme 1) is a readily
available building block whose synthetic utility remains
largely unexplored despite the early and elegant mechanistic
studies of Kirmse et al.[4] which pointed out its potential to
undergo highly stereospecific displacement reactions. It was
our intention to connect this simple synthon 4 to complex
structures such as 1 through anexpedient and stereospecific
route. Scheme 1 outlines the retrosynthetic plan devised to
accomplish this goal. Thus it was anticipated that structures of
type 1 could be derived from diolefin 2 by epoxidation,
followed by nucleophilic opening of the resulting epoxides.
Whereas stereospecificity during the epoxide openings was
highly desirable, random formation of these moieties was
preferred, at least initially, for optimal molecular diversity.
Diolefin 2 could, in turn, be obtained by tandem ring opening/
ring closing olefin metathesis of cyclobutene derivative 3 (see
Table 1 for physical properties) whose originfrom cis-3,4-
dichlorocyclobutene (4) and the hydroxytetrahydropyran
system 5 was evident. Such a route constitutes a rapid and
flexible access to complex molecular frameworks, which could
easily be modified to produce tailor-made intermediates for
total synthesis or compound libraries for biological screening
purposes.
cis-3,4-Dichlorocyclobutene as a Versatile
Synthon in Organic Synthesis. Rapid Entry into
Complex Polycyclic Systems with Remarkably
Stereospecific Reactions**
K. C. Nicolaou,* JuanA. Vega, and
Georgios Vassilikogiannakis
The frequent natural occurrence and wide-ranging bio-
logical activities of cyclic polyether-type structures has
stimulated considerable efforts directed toward their syn-
thesis.[1] Of particular interest are the aminoglycoside anti-
biotics represented by apramycin[2] and the marine neuro-
toxins represented by maitotoxin.[3] The former is of current
interest by virtue of its RNA-binding properties,[2] whereas
the latter constitutes a formidable synthetic challenge owing
to its unprecedented molecular complexity and size. Func-
tionalized polyether structures of type 1 (Scheme 1) embody
OH
NH2
H
H
H
H
O
O
epoxide formation
and opening
H
H
H
H
H
H
O
O
O
O
H
H
O
O
This strategy proceeded smoothly and, most importantly,
revealed a number of interesting reactivity patterns and
synthetic opportunities beyond the intended pathway. Hy-
droxytetrahydropyran 5 was prepared in enantiomerically
pure form from 6 by a modificationof a previously published
sequence.[5] Thus, benzylidine formation followed by regiose-
lective reductionwith DIBAL-H, Swernoxidation, Wittig
olefination, and DDQ-induced deprotection converted 6 into
5 ingood overall yield (Scheme 2).
H2N
HO
2
1
olefin
metathesis
nucleophilic
displacement
H
H
H
O
O
O
+
Cl
Cl
HO
O
O
H
H
H
4
5
3
Scheme 1. Retrosynthetic analysis of structures of type 1.
O
R
S
O
O
HO
HO
a)
O
some of the key features found in these natural products, and
as such they became targets inour investigations directed
toward such complex molecular architectures. Hereinwe wish
to report an expedient entry into these systems from readily
available starting materials by means of a series of stereo-
specific nucleophilic substitutions and an olefin metathesis
reaction.
MeO
6
7
b)
O
O
HO
c) – e)
HO
PMBO
5
8
[*] Prof. Dr. K. C. Nicolaou, Dr. J. A. Vega, Dr. G. Vassilikogiannakis
Department of Chemistry and
Scheme 2. Synthesis of 5. Reagents and conditions: a) MeOC6H4-
CH2(OMe)2 (1.1 equiv), CSA (1.1 equiv), MeCN, 258C, 10 h, 82%;
b) DIBAL-H (3.0 equiv), THF, À408C, 5 h, 80%; c) (COCl)2 (1.1 equiv),
DMSO (1.1 equiv), Et3N (1.2 equiv), CH2Cl2, À788C, 258C, 2 h, 91%;
d) CH3PPh3Br (1.1 equiv), NaHMDS (1.1 equiv), THF, 0 !258C, 1 h; then
aldehyde, 258C, 6 h, 75%; e) DDQ (1.2 equiv), CH2Cl2:H2O (10:1), 258C,
1 h, 95%. CSA ˆ 10-camphorsulfonic acid; DIBAL-H ˆ diisobutylalumi-
num hydride; DMSO ˆ dimethyl sulfoxide; NaHMDS ˆ sodium bis(tri-
methylsilyl)amide; DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡1)858-784-2469
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 GilmanDrive, La Jolla, CA 92093 (USA)
E-mail: kcn@scripps.edu
The reactionof cis-3,4-dichlorocyclobutene (4) with hy-
[**] We thank Drs. D. H. Huang and G. Siuzdak for their assistance with
NMR spectroscopy and mass spectrometry, respectively. This work
was financially supported by the National Institutes of Health (USA)
droxy tetrahydropyrancompoudn
5 was thenexplored.
Exposure of 4 to 1.1 equivalents of the sodium alkoxide
derived from 5 at 608C inTHF resulted inthe formationof
the diastereomeric monosubstituted cyclobutene derivatives 9
and 10 (Scheme 3; 80% yield, ca. 6:4 ratio). Heating of 9 or 10
or a mixture of the two inrefluxing toluene resulted ina clean
and The Skaggs Institute for Chemical Biology,
a postdoctoral
fellowship from the Skaggs Institute for Research (to V.G.), and
grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingel-
heim, Glaxo, Hoffmann-La Roche, DuPont, Merck, Novartis, Pfizer,
and Schering Plough.
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1433-7851/01/4023-4441 $ 17.50+.50/0
4441

COMMUNICATIONS
H
a)
H
H
H
O
4 + 5
O
Cl
Cl
O
a)
+
H
H
H
H
H
O
O
O
O
Cl
O
Cl
OH
H
b)
H
H
H
H
O
O
O
O
4
5
H
N
N
H
cis-10
cis-9
O
O
Cl
Cl
Ru
Ph
2
3
PCy3
b)
H
c)
A
c)
H
O
H
d)
O
O
H
H
d)
O
O
H
H
H
H
H
O
O
H
O
H
O
H
H
O
O
O
PhSe
Cl
NC
NC CN
CN
O
SePh
12
(E,Z)-11
(E,E)-13
15
(E,Z)-14
Scheme 3. Displacement reactions of cis-3,4-dichlorocyclobutene (4)
(syn SN2' vs. anti SN2'). Reagents and conditions: a) (syn SN2') NaH
(2.0 equiv), THF, 258C, 1 h; then 4 (1.1 equiv), 608C, 10 h, 80%; b) (con-
rotatory) toluene, 1108C, 3 h, 85 %; c) (anti SN2') PhSeCl (1.2 equiv), NaH
(2.2 equiv), DMF, 258C, 0.5 h, then 9 or 10, 258C, 6 h, 85%; d) (conrota-
tory). DMF ˆ N,N-dimethylformamide.
Scheme 4. Tandem ring opening/ring closing metathesis reaction and
conrotatory ring-opening Diels Alder reaction of cyclobutene derivative
3. Reagents and conditions: a) 5 (1.0 equiv), NaH (2.0 equiv), THF, 258C,
1 h; then 4 (0.5 equiv), 608C, 15 h, 85%; b) A (Grubbs× catalyst; 5 mol%),
toluene, 458C, 12 h, 80%; c) toluene, 1108C, 3 h, 90%; d) TCNE
(5.0 equiv), toluene, 1108C, 3 h, 72%.
conrotatory opening of the cyclobutene ring, thus leading to
absence of TCNE, whereas the C2-symmetric Diels Alder
product 15 was formed exclusively in72% yield inthe
presence of TCNE, again as a consequence of the stereo-
specificity of the reactions.
The diolefin 2 was epoxidized inthe desired random way by
reactionwith methyl(trifluoromethyl)dioxiraen, which was
generated in situ (CH3CN, 0 !258C),[10] to furnish all four
possible epoxides 16 19 (Scheme 5) in90% total yield and in
a ratio of approximately 1:1:1:1. Uponchromatographic
separation, three of these epoxides (16, 17, an d19) crystallized
the E,Z-chlorodiene system 11 (85% yield), whose geometry
was confirmed by 1H NMR spectroscopy (Jcis ˆ 7.0 Hz, Jtrans
ˆ
12.1 Hz).[4] This thermally induced reaction required relative-
ly high temperatures and was in accordance with the expected
cis stereochemistry of the cyclobutene derivatives 9 and 10.
Therefore, the displacement of chloride from 4 must have
followed a syn SN2' mechanism[4] inwhich the nucleophile
approached the cyclobutene ring from the same side as the
departing chloride ion. In contrast, the anti SN2' attack[6] of the
phenylselenyl anion on chlorobutene derivative 9 or 10 or a
mixture of the two to furnish directly the E,E-phenylseleno-
diene 13 (85% yield) is inferred on the basis of the known
propensity of trans-cyclobutene derivatives to open through a
conrotatory process at much lower temperatures than their cis
counterparts.[7] No phenylselenocyclobutene derivative 12
was detected in this displacement reaction, which suggests
both the anti SN2' mode of reactivity of PhSeÀ with the
chlorocyclobutenes 9 and 10 and the rapid conrotatory
opening of the presumed trans-1,2-phenylselenocyclobutene
12 to the E,E-phenylselenodiene 13 at ambient temperature.
Treatment of 4 with two equivalents of the sodium alkoxide
derived from 5 at 608C for 15 h gave 3 in85% yield
(Scheme 4; Table 1). The cyclobutene derivative 3 was then
exposed to the third-generation Grubbs× catalyst (A)[8] in
toluene at 458C to afford the desired tetracycle 2 in80%
Table 1. Selected physical properties of compounds 3, 16, an d22.
3: Colorless syrup; Rf ˆ 0.37 (silica gel, Et2O/hexane 1:1); [a]2D5 ˆ ‡50.8
(c ˆ 3.2, CHCl3); IR (film): nÄmax ˆ 2931, 2848, 1725, 1437, 1331, 1272, 1161,
1084, 990, 931, 831 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 6.29 (m, 2H),
6.09 (ddd, J ˆ 17.2, 11.7, 6.6 Hz, 1H), 6.02 (ddd, J ˆ 17.2, 11.7, 6.6 Hz, 1H),
5.35 (dt, J ˆ 17.2, 1.7 Hz, 2H), 5.19 (m, 2H), 4.65 (t, J ˆ 2.4 Hz, 1H), 4.61 (t,
J ˆ 2.6 Hz, 1H), 3.93 (m, 2H), 3.64 (m, 2H), 3.38 (m, 2H), 3.23 (m, 1H),
3.11 (m, 1H), 2.20 (m, 2H), 1.66 (m, 4H), 1.53 (m, 2H); 13C NMR
(125 MHz, CDCl3): d ˆ 142.7, 141.8, 137.0, 136.6, 116.3, 116.2, 81.5, 81.4,
81.0, 80.8, 77.8, 77.2, 67.3 (2 C), 30.7, 30.6, 25.4, 25.2; HRMS (MALDI):
‡
calcd for C18H26O4 [M‡Na ]: 329.1723, found: 329.1727
16: Colorless crystals; m.p. 146 1498C (Et2O/hexane 1:1); Rf ˆ 0.55 (silica
gel, Et2O/hexane 4:1); [a]D25 ˆ ‡10.4 (c ˆ 0.61, MeOH); IR (film): nÄmax
ˆ
2942, 2855, 1440, 1266, 1135, 1092, 1023, 955, 837, 793, 725 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 4.15 (d, J ˆ 10.2 Hz, 1H), 3.99 (m, 3H), 3.63 (d, J ˆ
4.4 Hz, 1H), 3.45 (m, 6H), 3.30 (d, J ˆ 3.6 Hz, 1H), 3.07 (m, 2H), 1.98 (m,
2H), 1.72 (m, 4H), 1.41 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 77.8,
75.4, 72.1, 71.0, 69.4, 68.9, 68.8, 68.7, 55.2, 55.1, 52.3, 50.4, 29.2, 29.0, 25.6,
yield. Despite close precedent for this olefin metathesis
‡
25.5; HRMS (MALDI): calcd for C16H22O6 [M‡Na ]: 333.1309, found:
[9]
reactionwith less sterically hindered substrates,
the first-
333.1302
ˆ
generation Grubbs' catalyst [(Cy3P)2Cl2Ru CHPh] failed to
induce the desired reaction. To explore the chemistry of
intermediates encountered on the way to the main target, a
solutionof compound 3 intoluene was heated at reflux inthe
absence and in the presence of tetracyanoethylene (TCNE).
As expected from the cis stereochemistry of the cyclobutene
derivative 3, the E,Z diene system 14 was the only product of
this conrotatory ring-opening reaction (90% yield) in the
22: Colorless crystals; m.p. 99 1018C (Et2O/hexane 1:1); Rf ˆ 0.17 (silica
gel, Et2O); [a]2D5 ˆ ‡39.4 (c ˆ 0.53, MeOH); IR (film): nÄmax ˆ 3412, 2931,
2860, 2096, 1325, 1261, 1090, 1043, 726 cmÀ1; 1H NMR (500 MHz, CDCl3):
d ˆ 4.38 (d, J ˆ 10.6 Hz, 1H), 4.24 (t, J ˆ 3.4 Hz, 1H), 4.00 (m, 4H), 3.85
(dd, J ˆ 5.5, 4.0 Hz, 1H), 3.71 (d, J ˆ 10.6 Hz, 1H), 3.50 (m, 6H), 3.14 (d,
J ˆ 6.2 Hz, 1H), 2.94 (d, J ˆ 4.7 Hz, 1H), 2.10 (m, 1H), 2.00 (m, 1H), 1.74
(m, 4H), 1.43 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 76.6, 75.4, 75.2,
72.5, 70.8, 68.4 (2C), 67.1, 67.0, 66.8, 61.5, 60.6, 29.4, 29.1, 25.2, 25.1; HRMS
‡
(MALDI): calcd for C16H24N6O6 [M‡Na ]: 419.1649, found: 419.1634
4442
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H
H
O
H
H
H
O
O
H
O
2
a)
H
H
O
H
H
H
O
H
H
H
O
H
H
O
H
O
O
O
O
H
H
O
H
O
H
H
H
O
H
H
H
H
H
O
O
O
O
O
O
O
O
H
O
O
O
O
O
H
16
b)
17
b)
18
b)
19
b)
OH
O
R
O
R
O
OH
O
H
H
H
H
H
H
H
H
R
H
R
OH
H
OH
H
O
O
O
O
H
H
H
H
H
H
H
H
H
O
R
O
O
O
H
H
R
H
H
O
O
O
R
O
HO
HO
OH
OH
R
20: R = N3
24: R = NH2
21: R = N3
25: R = NH2
22: R = N3
26: R = NH2
23: R = N3
27: R = NH2
d)
c)
c)
c) or d)
Scheme 5. Epoxidationof diolefin 2, regiospecific epoxide openings and synthesis of dihydroxy-diamino compounds 24 27. Reagents and conditions:
a) Na2EDTA (4 Â 10À4 m (aq.), 0.3 mol%), CF3COMe (40 equiv), NaHCO3 (30 equiv), oxone (20 equiv), MeCN, 0 !258C, 3 h, 90%; b) NaN3 (3.0 equiv),
NH4Cl (3.0 equiv), MeOH/H2O (7:1), 808C, 8 h, 88 92%; c) Et3P (5.0 equiv), CH3CN/H2O (9:1), 258C, 48 h, 85 91%; d) H2, Pd/C (10%), Et3N (5.0 equiv),
EtOH, 258C, 24 h, 77 81%. Na2EDTA ˆ ethylenediaminetetraacetic acid disodium salt.
from diethyl ether/hexane. The shown stereostructures were
assigned unambiguously by means of X-ray crystallographic
analysis (see Figure 1 for 16 and crystallographic data in
ref. [11] for 17 and 19).
Although the random formation of these epoxides (16 19)
was not unexpected, their opening reactions with NaN3
proved remarkably regio- and stereospecific. Thus, each of
these diepoxides (16 19) opened up in a unique way
either catalytic hydrogenation (10% Pd/C) or Et3P/H2O-
facilitated reduction.
The observed exclusivity inthe azide openings of epoxides
16 19 prompted us to examine this nucleophilic attack
further. Thus, the use of less reagent (1.5 equiv NaN3) in a
shorter time (2 h) inthe reactionof epoxide 16 resulted inthe
(Scheme 5) inthe presence of NaN
and NH4Cl inMeOH/
3
H2O (7:1) at 808C and led stereospecifically to a single
product (88 92% yield). Ineach reaction, the azide nucle-
ophile apparently attacked from the less sterically hindered
trajectory. As graphically depicted inFigure 1, the favorable
trajectories (a and b) for the opening of diepoxide 16 led to
the formationof diazide 20. The unfavorable 1,2-diaxial
interaction of the incoming azide nucleophile with the
hydrogenat C5 (trajectory c) adn the 1,2-pseudodiaxial
interaction with the bulky group at C9 (trajectory d) were
most probably responsible for the observed regiospecificity.
Applicationof the same ratioanles to diepoxides
17 19
provides anexplanationfor the observed regiospecific out-
come of these openings. The structures of these diazides were
fully established onthe basis of spectroscopic and X-ray
crystallographic analysis of 20, 21, an d23 (see ORTEP
drawing in Scheme 6 for 20 and crystallographic data in
ref. [11] for 21 and 23). The expected structure of diazodiol 22
was fully confirmed by HMQC experiments on the corre-
sponding bis(p-bromobenzoate) derivative, which was easily
prepared from diol 22 (4-bromobenzoyl chloride, Et3N,
4-dimethylaminopyridine, 258C, 4 h, 93%). Each of the
diazides obtained (20 23) was finally converted into the
targeted diaminodiols[12] (24 27, Scheme 5) ingood yield by
Figure 1. Postulated mechanistic rationale for the regiochemical outcome
of the NaN3 opening of diepoxide 16. Trajectories a and b are preferred
over trajectories c and d owing to less steric congestion. The conformation
derived from the X-ray crystallographic analysis of 16 is used.
Angew. Chem. Int. Ed. 2001, 40, No. 23
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4443

COMMUNICATIONS
Scheme 6. Further regiospecific openings of diepoxide 16 with different nucleophiles, and ORTEP drawings of products. Reagents and conditions: a) NaN3
(1.5 equiv), NH4Cl (1.5 equiv), MeOH/H2O (7:1), 808C, 2 h, 79%; b) NaN3 (1.5 equiv), NH4Cl (1.5 equiv), MeOH/H2O (7:1), 808C, 6 h, 90%; c) NaN3
(3.0 equiv), NH4Cl (3.0 equiv), MeOH/H2O (7:1), 808C, 8 h, 80%; d) NaH (2.2 equiv), PhSeCl (2.2 equiv), DMF, 1008C, 2 h, 79%; e) Et2AlCN (8.0 equiv),
toluene, 08C, 0.5 h, 75%.
regiospecific formationof moon-azide
28 in79% yield
organic synthesis and devised a short and highly efficient
route to complex and functionalized polyether systems
starting from 4. The methodology is expected to be useful in
synthetic applications and in the construction of molecular
diversity for biological screening.
(Scheme 6). Thus the sequence of attack on this diepoxide
was elucidated (trajectory a is more favorable thantrajector-
y b; Figure 1), which confirms the steric factors that govern
this reaction. The structure of 28 was confirmed by X-ray
crystallographic analysis[11] (see ORTEP drawing in
Scheme 6). Azide 28 was converted into the previously
Received: August 20, 2001 [Z17754]
obtained diazide 20 by further reaction(6 h) with NaN
3
(1.5 equiv) at 808C (90% yield). Increasing the steric demand
in the reaction by employing the bulkier phenylselenyl anion
[PhSeÀ, generated in DMF from PhSeCl and NaH] led to the
same regiochemical outcome as demonstrated by X-ray
crystallographic analysis of the resulting monoselenide 29
(see ORTEP structure inScheme 6). Finally, to probe the
questionof possible metal coordiantioneffects inthese
epoxide openings, epoxide 16 was exposed to excess Et2AlCN
intoluene at 0 8C. The result of this experiment, in which
complexationforces betweenthe aluminum and the oxygen
atoms of the substrate were expected to play a role, was again
a highly regio- and stereospecific diepoxide opening, which
led to dicyanodiol 30 in75% yield. The structure of 30 was
provenby X-ray crystallographic aanlysis (see ORTEP
structure in Scheme 6), which again underscores the dominant
role of steric effects withinthese diepoxide structures intheir
behavior toward nucleophilic reagents.
[1] For an adventure in total synthesis directed towards one of these
compounds, brevetoxin B, see: K. C. Nicolaou, Angew. Chem. 1996,
108, 644 664; Angew. Chem. Int. Ed. Engl. 1996, 35, 589 607.
[2] a) S. O×Connor, L. K. T. Lam, N. D. Jones, M. O. Chaney, J. Org.
Chem. 1976, 41, 2087 2092; b) S. Perzynski, M. Cannon, E. Cundliffe,
S. B. Chahwala, J. Davies, Eur. J. Biochem. 1979, 99, 623 628; c) R. Q.
Thompson, E. A. Presti, Antimicrob. Agents Chemother. 1967, 7, 332
340; d) R. Ryden, B. J. Moore, J. Antimicrob. Chemother. 1977, 3,
609 613.
[3] a) M. Murata, T. Iwashita, A. Yokoyama, M. Sasaki, T. Yasumoto, J.
Am. Chem. Soc. 1992, 114, 6594 6596; b) M. Murata, H. Naoki, T.
Iwashita, S. Matsunaga, M. Sasaki, A. Yokoyama, T. Yasumoto, J. Am.
Chem. Soc. 1993, 115, 2060 2062; c) M. Murata, H. Naoki, S.
Matsunaga, M. Satake, T. Yasumoto, J. Am. Chem. Soc. 1994, 116,
7098 7107; d) M. Satake, S. Ishida, T. Yasumoto, J. Am. Chem. Soc.
1995, 117, 7019 7020; e) M. Sasaki, N. Matsumori, T. Maruyama, T.
Nonomura, M. Murata, K. Tachibana, T. Yasumoto, Angew. Chem.
1996, 108, 1782 1785; Angew. Chem. Int. Ed. Engl. 1996, 35,
1672 1675; f) T. Nonomura, M. Sasaki, N. Matsumori, M. Murata,
K. Tachibana, T. Yasumoto, Angew. Chem. 1996, 108, 1786 1789;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1675 1678; g) W. Zheng, J. A.
In conclusion, we have demonstrated the versatility of cis-
3,4-dichlorocyclobutene (4) as a useful building block in
4444
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COMMUNICATIONS
DeMattei, J.-P. Wu, J. J.-W. Duan, L. R. Cook, H. Oinuma, Y. Kishi, J.
Am. Chem. Soc. 1996, 118, 7946 7968.
[4] W. Kirmse, F. Scheidt, H.-J. Vater, J. Am. Chem. Soc. 1978, 100, 3945
3946.
[5] K. C. Nicolaou, C.-K. Hwang, B. E. Marron, S. A. DeFrees, E. A.
Couladouros, Y. Abe, P. J. Carroll, J. P. Snyder, J. Am. Chem. Soc.
1990, 112, 3040 3054.
[6] For previous reports of such reactions see: a) G. Stork, W. N. White, J.
Am. Chem. Soc. 1956, 78, 4609 4624; b) G. Stork, A. F. Kreft III, J.
Am. Chem. Soc. 1977, 99, 3850 3851; c) R. M. Magid, O. S. Fruchey, J.
Am. Chem. Soc. 1977, 99, 8368 8370.
complexes are efficient catalysts for the enantioselective
hydrogenation of unfunctionalized alkenes,[2] a class of sub-
strates that gives unsatisfactory results with other catalysts.[3]
The best enantioselectivities (up to 99% ee) have been
observed for 1-alkyl-1,2-diaryl-substituted alkenes, while
other alkenes such as monoaryl-1,2-dimethyl-substituted
alkenes are converted with only moderate enantiomeric
excesses. Here we report a new class of ligands, the
phosphinite oxazolines 2, which induce high enantioselec-
tivity with a much broader range of alkenes and, thus,
significantly enhance the scope of Ir-catalyzed hydrogenation.
Both enantiomers of the phosphinite oxazoline ligands 2
are readily prepared inthree to four steps, starting from
imidates 5 or carboxylic acids 8 and l-serine methyl ester
hydrochloride (4) or the corresponding d isomer (Scheme 1).
Special precautions had to be taken in the peptide coupling
[7] G. Maier, A. Bothur, Eur. J. Org. Chem. 1998, 2063 2072.
[8] For the preparationof this catalyst see: M. Scholl, S. Ding, C. W. Lee,
R. H. Grubbs, Org. Lett. 1999, 1, 953 956.
[9] a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc.
1996, 118, 6634 6640; for selected reviews onthe olefinmetathesis
reaction, see: b) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34,
18 29; c) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413 4450;
d) T. J. Katz, Adv. Organomet. Chem. 1977, 16, 283 317.
[10] D. Yang, M.-K. Wong, Y.-C. Yip, J. Org. Chem. 1995, 60, 3887 3889.
[11] Crystallographic data (excluding structure factors) for the structures
reported inthis paper have beendeposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. S
CCDC-168813 168821. Copies of the data canbe obtained free of
charge onapplicationto CCDC, 12 UinonRoad, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
[12] Interestingly, the spectroscopic data of diaminodiols 24 27 reveal the
complexationwith one molecule of either Et 3N or Et3P, depending on
the protocol used for their preparation(10% Pd/C, Et 3N or Et3P/
H2O).
A New Class of Modular Phosphinite
Oxazoline Ligands: Ir-Catalyzed
Enantioselective Hydrogenation of Alkenes**
Jˆrg Blankenstein and Andreas Pfaltz*
Phosphinooxazolines 1 (phox ligands) have been success-
fully applied in many different enantioselective metal-cata-
lyzed processes.[1] We have recently found that iridium phox
Scheme 1. Synthesis of compounds
2
for which R3 ˆ Ph. a) 4,
ClCH2CH2Cl, reflux; b) R2MgX, À788C; c) nBuLi, NEt3, ClPPh2,
À788C; d) 4, EDC, HOBT, CuCl, DMF; e) R2MgX, À788C; f) (1) NEt3,
TsCl, (2) H2O. EDC ˆ N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride, HOBTˆ 1-hydroxybenzotriazole.
[*] Prof. A. Pfaltz, Dr. J. Blankenstein
Department Chemie
Universit‰t Basel
St.-Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (‡41)61-2671103
(step d) to avoid racemization.[4] The additionof Grignard
reagents to 9 sometimes gave complex mixtures, so that in
general the (hydroxymethyl)oxazolines 7 were preferentially
synthesized by means of the imidate route.[5] The modular
nature of 2 with its three permutable structural units (R1, R2,
and the P-substituents) is an attractive feature of these
ligands. Especially the selection of the R1 group, which is
derived from a carboxylic acid, is essentially unlimited.
E-mail: andreas.pfaltz@unibas.ch
[**] We thank Dr. Martin Studer and Dr. BenoÓt Pugin (Solvias AG, Basel)
for fruitful discussions, and Prof. Kevin Burgess (Texas A&M
University) for preprints of related unpublished work. Financial
support by the Swiss National Science Foundation is gratefully
acknowledged.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2001, 40, No. 23
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4023-4445 $ 17.50+.50/0
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