Efficient enantioselective synthesis of functionalized tetrahydropyrans by Ru-catalyzed asymmetric ring-opening metathesis/cross-metathesis (AROM/CM)

Article abstract of DOI:10.1021/ja0458672

An efficient method for enantioselective synthesis of highly functionalized pyrans (up to 98% ee) through Ru-catalyzed asymmetric ring-opening metathesis/cross-metathesis is described. Reactions are promoted by a recyclable chiral Ru-chloride or a new chiral Ru-iodide complex; the latter catalyst is less efficient but gives rise to significantly higher levels of enantioselectivity. Catalytic reactions can be performed in undistilled solvent and with a wide range of substrates, including those that contain secondary and tertiary alcohols. Representative regioselective functionalizations that highlight the utility of the catalytic method are also presented. Copyright

Full text of DOI:10.1021/ja0458672

Published on Web 09/14/2004
Efficient Enantioselective Synthesis of Functionalized Tetrahydropyrans by
Ru-Catalyzed Asymmetric Ring-Opening Metathesis/Cross-Metathesis
(AROM/CM)
Dennis G. Gillingham, Osamu Kataoka, Steven B. Garber, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received July 9, 2004; E-mail: amir.hoveyda@bc.edu
Table 1. Ru-Catalyzed AROM/CM of 2a-d with Styrene
Recent research in these laboratories has led to the development
of chiral Mo-1 and Ru-based complexes2 that promote asymmetric
olefin metathesis reactions; the resulting methods offer unique and
efficient pathways for the preparation of versatile optically enriched
organic molecules.3 Our investigations have been partly concerned
with the development of catalytic asymmetric ring-opening/cross-
metathesis reactions (AROM/CM), since catalytic ring-opening
metathesis has proven to be of significant value in organic
synthesis.4 A reason for the potential of catalytic AROM/CM is
that it may allow direct access to heterocyclic structures in high
optical purity.5 Thus far, however, nearly all Mo- or Ru-catalyzed
AROM/CM processes have involved transformations of strained
norbornenes that deliver functionalized cyclopentanes.
Herein, we report efficient and highly enantioselective Ru-
catalyzed AROM/CM reactions of significantly less strained
oxabicyclic olefins; these transformations allow access to a wide
range of 2,6-disubstituted pyrans,6 building blocks found in
numerous biologically significant molecules.7 Catalytic AROM/
CM reactions afford functionalized pyrans in up to 98% ee, are
performed at ambient temperature, and do not require solvent.8
Transformations are catalyzed by 1-5 mol % 1a and a new complex
1b; similar to 1a, Ru-iodide 1b is air stable. We provide data
demonstrating that 1b initiates reactions with significantly higher
asymmetric induction than those obtained with chloride 1a.
recycled
time (h);
conversion (%)a
mol %
yield
(%)c
catalyst
yield (%)c
ee
entry
R
1a
productb
(%)d
1
H
H
2a
2a
2b
2c
1.5; >98
12; >98
1; >98
0.8; >98
1; >98
5
1
5
5
5
4a
4a
4b
4c
4d
80
74
70
71
81
94
<5
65
70
96
94
94
96
86
46
2e
3
Bn
Me
TBS 2d
4
5
a Determined by 1H NMR analysis. b Trans olefin (>98%). c Isolated
yields of purified products. d Determined by chiral HPLC and 1H NMR
(see Supporting Information for details). e Reaction carried out in a 0.2 M
solution of THF (vs 0.1 M).
Table 2. Ru-Catalyzed AROM/CM of 2a with Various Olefins
recycled
time (h);
yield
catalyst
ee
entry
R1
conversion (%)a productb (%)c yield (%)c (%)d
1
p-OMeC6H4 3b 1a
1; >98
9; >98
5
5
6
6
7
7
8
8
9
9
78
69
68
60
70
68
43
70
72
58
85
30
55
20
50
30
62
25
<5
58
80
96
88
98
86
95
90
94
60
59
2e p-OMeC6H4 3b 1b
3
4
5
6
7
8
p-CF3C6H4 3c 1a
p-CF3C6H4 3c 1b
1; >98
12; >98
3.5; >98
15; >98
2; >98
p-BrC6H4
p-BrC6H4
o-MeC6H4
o-MeC6H4
3d 1a
3d 1b
3e 1a
3e 1b
As illustrated in entry 1 of Table 1, reaction of unsaturated
bicyclic alcohol 2a9 proceeds readily at 22 °C to >98% conversion
in 90 min with 5 mol % 1a to afford 4a in 94% ee and 80% isolated
yield.10 In the presence of 1 mol % 1a, the desired pyran is
generated in 94% ee and 74% isolated yield (entry 2), albeit at a
slower rate. Ru-catalyzed enantioselective desymmetrization of
benzyl ether 2b proceeds to completion in 1 h to afford 4b in 96%
ee (entry 3). As shown in entry 4 of Table 1, methyl ether 4c is
generated efficiently in 86% ee. However, Ru-catalyzed desym-
metrization of silyl ether 2d delivers 4d in only 46% ee (entry 5).
In most cases shown in Table 1, complex 1a is recovered in good
yield (see below for recycling studies).
18; >98
9e Cy
3f 1a 13.5; 96
3f 1b
10f Cy
2; 98
a-d See Table 1. e Reactions carried out in dichloroethane. f Reaction run
neat.
studies involved reactions promoted by Ru complex 1a; the
corresponding data are summarized in entries 1, 3, 5, 7, and 9 of
Table 2. When electron-rich (entry 1) or electron-poor styrene
partners (entries 3 and 5) are used, olefin metatheses proceed to
>98% conversion within a few hours to afford the desired pyrans
in 80-88% ee and 68-78% yield (after chromatography). Catalytic
AROM/CM with the sterically demanding styrene 3e (entry 7)
affords pyran 8d in 90% ee and only 43% yield, likely because the
slower reacting terminal olefin allows oligomerization of 2a to
Because of the efficiency and enantioselectivity in reactions of
alcohol 2a (entries 1 and 2, Table 1), and since the corresponding
products can be converted to other derivatives, the Ru-catalyzed
AROM/CM of this substrate was further investigated. Initially, our
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C O M M U N I C A T I O N S
become a competitive pathway.11 Catalytic desymmetrization in the
presence of the aliphatic olefin in entry 9 is slower than those with
styrenes, affording the desired pyran in 60% ee.12
Table 3. Ru-Catalyzed AROM/CM of 10 Promoted by Complexes
1a-b
Although the reactions in Table 2 proceed with appreciable
enantioselectivity, the levels of optical purity are lower than those
seen with the reaction of 2a and styrene (entries 1 and 2, Table 1).
To address this shortcoming, we decided to synthesize and examine
the catalytic activity of chiral iodide complex 1b. This initiative
was inspired by a disclosure by Grubbs,2c who reported that addition
of NaI to a solution of a chiral Ru-dichloride phosphine complex
in certain cases leads to enhancement in enantioselectivity of ring-
closing metathesis. The increase in asymmetric induction was
attributed to the formation of a Ru-diiodide, although a discrete
carbene was not isolated and characterized. Since Ru complexes
bearing bidentate aryl carbenes are stable to silica gel chromatog-
raphy,13 we decided to synthesize, purify, and utilize chiral iodide
complex 1b and determine unambiguously whether it can promote
AROM/CM processes with improved enantioselectivity (compared
to 1a).
recycled
time (h);
catalyst
yield
(%)c
catalyst; conversion
yield
ee
entry
R
R1 (olefin)
mol (%)
(%)a
productb (%)c
(%)d
1
2e
3
4
5
6
7
H
H
10a Ph
10a Ph
Bn 10b Ph
Bn 10b Ph
1a; 2
3; >98 11
60
85
87
85
74
79
87
98
52
61
75
91
56
74
77
67
<5
83
<5
22
75
71
56
31
69
83
79
90
66
92
73
91
70
81
63
93
1b; 5 3; >98 11
1a; 2 6; >98 12
1b; 5 36; >98 12
3; >98 13f
Bn 10b p-OMeC6H4 1a; 2
Bn 10b p-OMeC6H4 1b; 5 5; >98 13
Bn 10b p-CF3C6H4 1a; 2
3; >98 14
8e Bn 10b p-CF3C6H4 1b; 5 5; 98
14
15
9
Bn 10b Cy
1a; 5 15; 98
We prepared chiral complex 1b as a light brown powder by
treatment of 1a with NaI (THF, 70 °C). Formation of 1b is indicated
by the presence of a signal corresponding to a new Ru carbene in
10e Bn 10b Cy
11 TBS 10b Ph
12e TBS 10b Ph
1b; 5 2; >98 15
1a; 5 3; >98 16
1b; 5 3; >98 16
1
the H NMR spectrum (RudCH at 15.57 ppm vs 16.04 ppm for
a-d See Table 1. e Reactions run neat. f E:Z ) 9:1.
Table 4. Ru-Catalyzed AROM/CM of Tertiary Alcohol 17
1a); an X-ray structure of 1b has been obtained (see above).
Subsequent studies indicate that, although 1b is less active than
1a, it effectively initiates AROM/CM. Importantly, as illustrated
in eq 1 (2df4d), Ru-iodide 1b promotes AROM/CM of 2d with
styrene in significantly higher asymmetric induction compared to
chloride complex 1a (84 vs 46% ee). We have established that, as
the data in entries 2, 4, 6, and 8 of Table 2 illustrate (see below
also), the ability of 1b to effect AROM/CM of oxabicyclic alcohol
2a with higher (often substantially) enantioselectivity extends to
most other olefin partners; only in reactions shown in entries 9
and 10 is the enantioselectivity not enhanced with complex 1b.
recycled
catalyst
time (h);
yield
ee
entry
R1
catalyst conversion (%)a productb (%)c yield (%)c (%)d
1
2
3
4
5
6
Ph
Ph
3a
3a
1a
1b
3; >98
48; 86
2; >98
48; >98
3; >98
48; 86
18
18
19
19
20
20
78
58
72
60
75
60
60
<5
55
<5
58
71
92
68
88
74
92
p-OMeC6H4 3b 1a
p-OMeC6H4 3b 1b
p-CF3C6H4 3c
p-CF3C6H4 3c
1a
1b
<5
a-d See Table 1.
Several additional attributes of the Ru-catalyzed method are
worthy of note: (1) Chiral Mo-based complexes1 readily promote
polymerization reactions, under a variety of conditions, with the
representative substrates examined in Tables 1-4. (2) Reactions
can be carried out in commercial-grade, undistilled THF. (3) In
many instances, when reactions are carried out in solvent (e.g., Table
4), the yield of recovered 1b is lower than that of 1a. This is likely
because the less reactive complex 1b requires longer reaction times,
which lead to the release of substantially larger amounts of the
active Ru carbene; previous studies show that, with this class of
chiral catalysts, the active Ru complex does not return to the styrene
ether ligand.2b Consistent with the above proposal, when reactions
are run neat, conditions that require shorter times (Table 3), the
yield of recovered 1b is typically increased. (4) Chiral catalyst 1a
can be isolated after each reaction and reused for up to five cycles
to promote highly enantioselective metathesis reactions (see Sup-
porting Information for details).
As indicated by the data in Table 1, enantioselectivities can vary
significantly as a result of a small structural modification within a
substrate. Accordingly, to establish the generality of this class of
Ru-catalyzed transformations, we examined the AROM/CM of exo
alcohol 10a and its derived ethers (Table 3); catalytic transforma-
tions of tertiary alcohol 17 were also investigated (Table 4). Ru-
catalyzed AROM/CM of the exo alcohol and ethers 10a-d proceed
efficiently in the presence of 2 mol % 1a and electron-rich (entries
1, 3, 5, and 11, Table 3) or electron-deficient styrenes (entry 7) as
well as aliphatic terminal olefins (entry 9). Nonetheless, enantio-
selectivity levels are lower than those observed in reactions of endo
alcohol 2a and its derived ethers (Tables 1 and 2). However, as
also shown in Table 3, with these exo-substituted alcohols and
ethers, Ru-iodide 1b promotes AROM/CM with significantly
higher asymmetric induction (entries 2, 4, 6, 8, 10, and 12). Similar
observations are made in the case of transformations of tertiary
alcohol 17 (Table 4). In nearly all cases, the chiral complex 1b
elevates the catalytic AROM/CM protocol from a method that
delivers 2,6-disubstituted pyrans with moderate levels of optical
purity (e90% ee) to one that allows access to the same heterocyclic
structures often in >90% ee.
That Ru-catalyzed AROM/CM can be run neat becomes a
particularly notable advantage with substrates that do not easily
undergo reaction in solution. For example, whereas the reactions
in Scheme 1 proceed to <2% conversion after 24 h in solution
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C O M M U N I C A T I O N S
Scheme 1. Ru-Catalyzed AROM/CM of Less Reactive Substrates
in the Absence of Solvent (<2% Conversion in Solution)
reduction of 11 and functionalization of the resulting syn-1,3-diol
lead to homoallylic alcohol 30 (via 29), an intermediate employed
in a recent asymmetric synthesis of natural product 31.17 The fully
functionalized pyran 33, obtained in 80% ee (9:1 E:Z) by Ru-
catalyzed AROM/CM of 32 with styrene (neat) can be converted
to optically enriched diol 34, a synthon for the total synthesis of
natural polypropionates,18 as a single diastereomer and olefin regio-
and stereoisomer.
Future studies will include the synthesis and development of more
effective chiral Ru catalysts for olefin metathesis, examination of
the mechanism of these and related catalytic asymmetric processes,
as well as applications of the newly developed protocols to total
synthesis of complex molecules.
Acknowledgment. Financial support was provided by the NSF
(CHE-0213009). We thank Materia, Inc., for gifts of Ru complexes
and J. J. Van Veldhuizen, G. A. Cortez, and M. K. Brown for
helpful suggestions. We are grateful to K. S. Griswold for assistance
in determining the X-ray structure of Ru complex 1b.
Scheme 2. Representative Functionalizations of AROM/CM
Products
Supporting Information Available: Experimental procedures and
spectral and analytical data for reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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with 2 mol % 1a, in the absence of solvent, oxabicycles 21, 23,
and 25 readily undergo AROM/CM to afford 22, 24, and 2614 in
<2 h in 93, 80, and 80% ee, respectively. Furthermore, when the
less reactive 1b is used (2 mol %), >98% conversion is achieved
in longer reaction times but with notably higher enantioselectivity
(98, 94, and 93%, respectively).15
Optically enriched pyrans obtained through the present catalytic
protocol can be functionalized with excellent regioselectivity in a
variety of ways. The sequence illustrated in Scheme 2 involving
the conversion of 4a to primary alcohol 28, an intermediate
synthesized previously in the course of a total synthesis of
leucascandrolide,16 is one case in point. In addition to enantio-
selective synthesis of pyrans, the Ru-catalyzed protocol provides
access to highly functionalized acyclic building blocks that can be
used in the synthesis of biologically active compounds. Two
representative cases are depicted in Scheme 2. Dissolving metal
(11) When o-bromostyrene is used, only polymerization of 2a is observed.
(12) Oligomerization of substrate occurs in these reactions; optimal yields are
obtained by slow addition of 2a to a mixture of 1a and the aliphatic olefin.
(13) (a) Kingsbury, J. S.; Harrity, J. P. A.; Hoveyda, A. H. J. Am. Chem. Soc.
1999, 121, 791-799. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.;
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A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S.
B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biol. Chem. 2004, 2, 8-23.
(14) Secondary alkyl halides can be readily functionalized by metal-catalyzed
cross-coupling reactions. See: Powell, D. A.; Fu, G. C. J. Am. Chem.
Soc. 2004, 126, 7788-7789 and references therein.
(15) Effective dissolution of substrates was achieved with 5 equiv of 3a. Control
experiments indicate that high conversion is not due to increased amounts
of 3a (5 vs 2 equiv).
(16) Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833-6849.
(17) Tosaki, S.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org. Lett. 2003, 5,
495-498.
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