Ring-closing metathesis in carbohydrate annulation

Article abstract of DOI:10.1002/(SICI)1521-3773(19981217)37:23<3298::AID-ANIE3298>3.0.CO;2-O

Even eight-membered rings (such as in 2) can be formed by ring-closing metathesis of glucose derivatives P such as 1. Enantiomerically pure tricyclic spiro compounds can also be prepared.

Full text of DOI:10.1002/(SICI)1521-3773(19981217)37:23<3298::AID-ANIE3298>3.0.CO;2-O

COMMUNICATIONS
H
H
Ring-Closing Metathesis in Carbohydrate
Annulation**
OMe
OH
O
O
Ph
O
David J. Holt, William D. Barker, Paul R. Jenkins,*
David L. Davies, Shaun Garratt, John Fawcett,
David R. Russell, and Subtrata Ghosh
5, 15%
b
H
H
H
H
OMe
OH
OMe
OH
O
O
O
a
O
O
+
The Chiron Approach to the synthesis of chiral target
molecules from carbohydrates is now a well established
component in the armoury of organic chemistry.[1] A key
element of this strategy is the range of methods available for
the synthesis of cyclic compounds that include some or all of
the carbon atoms of the original carbohydrate.[2] We have
made several contributions to this area of carbohydrate
annulation by using Robinson annulation,[3] aldol condensa-
tion,[4] radical cyclization,[5] and through the application of
these ideas to the synthesis of a C-ring synthon of taxol.[6] In
recent times there has been considerable interest in new
applications of the ring-closing metathesis (RCM) reaction[7]
by using the Grubbs catalyst 1.[8] Car-
O
O
Ph
Ph
H
H
OMe
O
O
O
4, 53%
3, 33%
O
Ph
H
O
H
O
OMe
OH
OMe
OH
O
2
c
+
O
Ph
O
Ph
H
H
7, 15%
6, 74%
b
b
H
O
H
OMe
OH
OMe
OH
O
O
O
O
O
Ph
Ph
H
H
8, 89%
9, 80%
P(C6H11
)
3
bohydrate substrates have been sub-
jected to RCM to produce oxygen and
nitrogen heterocyclic sugar deriva-
tives.[9] The formation of macrocyclic
lactones on sugar substrates in a RCM
reaction was first reported by De-
scotes[10] using a tungsten catalyst.
ˆ
Scheme 1. Reagents and conditions: a) H2C CHMgCl, THF, reflux, 2 h;
b) [RuCl2(CHPh){P(C6H11)3}2] (1), benzene, 608C, 48 h for 5 and 17 h for 8
Cl
Cl
Ph
H
Ru
ˆ
and 9; c) H2C CHCH2MgCl, THF, 2 h.
P(C6H11
)
3
5-6 ring system in the product. However, a 15% yield of 5 was
obtained in the RCM reaction of 3, along with 75% of
recovered starting material. In addition to the usual spectro-
scopic characterization an X-ray crystal structure of 5 was
obtained.[12]
Addition of allylmagnesium chloride to ketone 2 furnished
the cis diene 6 (74%) and the trans diene 7 (15%). Both 6 and
7 underwent ring-closing metathesis to produce the annulated
sugar derivatives 8 and 9 in yields of 89 and 80%, respectively.
An X-ray crystal structure of 8 was obtained.[16] Clearly there
is no steric impediment to the formation of the cis and trans
6-6 ring systems in 8 and 9, respectively.
While the addition of an allyl Grignard reagent to ketone 2
gives the b-alcohol 6 as the major product, the addition of the
vinyl Grignard reagent gives the a-alcohol 4 as the major
product. This strange reversal in the stereoselectivity deserves
some comment. The major difference between vinyl and allyl
Grignard reagents is that allylic rearrangement is possible
during the addition of an allyl Grignard compound to a
ketone. We believe that allylic rearrangement is best accom-
modated by an axial attack of allylmagnesium chloride on
ketone 2 to afford the b-alcohol 6 as the major product. With
vinylmagnesium chloride, however, there is a small preference
in favor of a-attack to give the alcohol 4.
A recent publication[17] has highlighted the difficulty of
synthesizing eight-membered rings with the normal ring
closure methods, and reported the use of the Claisen
rearrangement in the conversion of d-glucose into an
enantiomerically pure cyclooctenone. The synthesis of eight-
membered carbocyclic and heterocyclic rings by RCM has
been reported by Grubbs.[18a] Further examples have also
appeared,[18b] and include the total synthesis of dactylol[18c] and
the preparation of eight-membered ether rings in a sequence
starting from glyceraldehydacetonide using a molybdenum
catalyst for the RCM reaction.[18d] Scheme 2 illustrates the
1
More recently lactonization using the Grubbs catalyst 1 has
been reported,[11] along with applications in the synthesis of
tricolorinA[12] and (‡)-cyclitophellitol from xylose.[13]
As part of our continuing program on new methods for
carbohydrate annulation we became interested in the appli-
cation of RCM in the preparation of carbocyclic- and
spiroannulated sugars to produce methods that could be
applied in our synthetic route to taxoids[14] and other natural
products. We report here our studies on the synthesis of five-,
six-, and eight-membered annulated sugars along with spiro
systems.
The starting material was the ketone 2 (Scheme 1), a
derivative of methyl-a-d-glucopyranoside.[15] Reaction with
vinylmagnesium chloride gave a mixture of allylic alcohols 3
(33%) and 4 (53%). RCM with the Grubbs ruthenium
catalyst[8] was not successful on the diene 4, probably because
of the steric strain that would be produced in the trans-fused
[*] Dr. P. R. Jenkins, D. J. Holt, W. D. Barker, Dr. D. L. Davies,
S. Garratte, Dr J. Fawcett, Dr. D. R. Russell
Department of Chemistry, Leicester University
Leicester LE1 7RH (UK)
Fax: (‡44)116-252-3789
E-mail: kin@le.ac.uk
Prof. S. Ghosh
Indian Association for the Cultivation of Science
Department of Organic Chemistry
Calcutta 700032 (India)
[**] This work was supported by the Engineering and Physical Sciences
Research Council, Pharmachemie BV, Haarlem, Holland, and the
Indian National Science Academy ± Royal Society study visit grant to
S. Ghosh.
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the
author.
3298
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3723-3298 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 23

COMMUNICATIONS
H
H
H
H
H
H
conversion into the allyl ether 19 furnished the RCM
substrate in 72% yield. This compound underwent RCM to
give the spiro-fused dihydropyran system 20 in 73% yield.
The structure of 20 was confirmed by X-ray crystal structure
analysis.[16]
OMe
OH
OMe
O
O
O
OMe
OH
O
O
O
O
a
+
O
Ph
O
O
Ph
Ph
2
10, 13%
11, 7%
b
b
In conclusion we have shown that ring-closing metathesis is
an effective method for the annulation of glucose derivatives.
Further studies are underway on the utilization of the
enantiomerically pure annulated products in organic syn-
thesis.
H
O
H
O
OMe
OH
OMe
OH
O
O
O
O
Ph
Ph
H
H
13, 26%
12, 44%
ˆ
Scheme 2. Reagents and conditions: a) H2C CH(CH2)3MgCl, THF, re-
flux, 4 h; b) [RuCl2(CHPh){P(C6H11)3}2] (1), benzene, 31 h at 608C for 10,
and 17 h at 608C for 11.
Experimental Section
All rections were performed under nitrogen. Solvents were dried by using
standard methods. The yields reported refer to products purified by column
chromatography.
cyclooctaannulation of ketone 2 by RCM. The addition of the
pentenyl Grignard reagent to the ketone 2 led to alcohols 10
and 11 in yields of 13 and 7%, respectively, along with a
recovery of 37% starting material and 37% of a single alcohol
that arises from reduction of the ketone 2.[19] Dienes 10 and 11
were then treated with 9 mol% of catalyst 1 in benzene for 31
and 41 hours, respectively. This led to the cyclooctene
derivatives 12 (44% yield with 32% recovered starting
material) and 13 (26% yield with 48% recovered starting
material). The assignment of structure 12 was confirmed by
X-ray crystal structure analysis. The crystals were all weak
diffractors, but the assignment of structure 12 was unambig-
uous.[16]
Methods for the synthesis of spiro-fused tetrahydrofuran or
pyran ring systems are based on the addition of an appropriate
reagent to a ketone, followed by spiroether formation,[20a]
intramolecular radical addition,[20b] and intramolecular reac-
tion of an oxonium ion on an allyl silane.[20c] The preparation
of enantiomerically pure spiro products is achieved by starting
from an enantiomerically pure ketone.[20d] We have applied
RCM to the problem of spiroannulation (Scheme 3).[21] The
starting point was the ketone 14, a derivative of methyl-a-d-
glucopyranoside.[22] Addition of vinylmagnesium chloride
gave the allyl alcohol 15 in 75% yield. Deprotonation with
sodium hydride, followed by allylation with allyl bromide
furnished the ether 16 in 77% yield. Ring-closing metathesis
of diene 16 gave the spiro-fused tricyclic compound 17 in 75%
yield. The structure of 17 was confirmed by X-ray crystal
structure analysis.[16] The equivalent reaction sequence with
allylmagnesium chloride was also successful. Ketone 14 was
converted into alcohol 18 in 65% yield, and subsequent
Typical synthetic procedure for the ruthenium catalyzed RCM reaction:
Nitrogen gas was bubbled for 2 ± 3 minutes through a solution of the
diolefin 7 (86 mg, 0.25 mmol) in benzene (10 mL). The catalyst 1 (4 mol%)
was then added and the mixture heated at 60oC for 17 h. The solvent was
then removed under reduced pressure, and the crude reaction mixture
purified by column chromatography (silica gel, petroleum ether (40 ±
60oC)/diethyl ether (3/1 !2/1) to yield the cyclohexaannulated sugar
derivative 9 as a colorless oil (63 mg, 80%).
Physical and spectroscopic data for 9: [a]1D8 ˆ ‡8.8 (c ˆ 6.0 in CHCl3); Rf ˆ
1
0.13, petroleum ether (40 ± 60oC)/diethyl ether (1/1); H NMR (250 MHz,
CDCl3): d ˆ 7.51 ± 7.33 (m, 5H, Ph), 5.76 (m, 1H, 9-H), 5.60 (m, 1H, 8-H),
5.53 (s, 1H, 11-H), 4.39 (s, 1H, 1-H), 4.25 (dd, J ˆ 3.6, 9.0 Hz, 1H, 6 eq-H),
3.93 ± 3.77 (t, J ˆ 9.0 Hz, 1H, 6 ax-H; m, 1H, overlapping, 5-H), 3.65 (t, J ˆ
10.6 Hz, 1H, 4-H), 3.41 (s, 3H, OMe), 2.60 (m, 1H, CHH, 7-H), 2.47 (m,
1H, CHH, 10-H), 2.16 (dt, J ˆ 5.2, 10.6 Hz, 1H, 3-H), 2.04 (s, 1H, OH), 2.02
(m, 1H, overlapping, CHH, 10-H), 1.86 (dd, J ˆ 4.4, 18.2 Hz, 1H, CHH,
7-H); 13C NMR (62.9 MHz, CDCl3): d ˆ 138.2 (C, Ph), 129.3 (CH, Ph),
128.6 (CH, Ph), 126.5 (CH, Ph), 126.1 (CH, C9), 123.5 (CH, C8), 103.3 (CH,
C1), 102.3 (CH, C11), 80.2 (CH, C4), 71.9 (C, C2), 69.7 (CH2, C6), 64.5
(CH, C5), 55.5 (CH3, OMe), 37.6 (CH, C3), 34.3 (CH2, C7), 24.4 (CH2,
‡
‡
C10); HR-MS (FAB): m/z(%): 319 (34) [MH ]; calcd for C18H23O5 [MH ]:
319.1546; found: 319.1544.
Received: May 15, 1998 [Z11866IE]
German version: Angew. Chem. 1998, 110, 3486 ± 3488
Keywords: annulation ´ carbohydrates ´ homogeneous cat-
alysis ´ metathesis ´ ruthenium
[1] S. Hanessian, Total Synthesis of Natural Products; The Chiron
Approach, Pergamon, Oxford, 1993.
[2] R. J. Ferrier, S. Middleton, Chem. Rev. 1993, 93, 2779; J. C. Lopez, B.
Fraser-Reid, Chem. Commun. 1997, 2251.
[3] R. V. Bonnert, P. R. Jenkins, J. Chem. Soc. Chem. Commun. 1987, 6;
R. V. Bonnert, J. Howarth, P. R. Jenkins,
N. J. Lawrence, J. Chem. Soc. Perkin Trans. 1
1991, 1225.
H
H
H
O
OMe
O
OMe
O
OMe
O
O
O
a
b
c
[4] A. J. Wood, P. R. Jenkins, J. Fawcett, D. R.
Russell, J. Chem. Soc. Chem. Commun.
1995, 1567.
[5] R. V. Bonnert, M. J. Davies, J. Howarth,
P. R. Jenkins, J. Chem. Soc. Chem. Com-
mun. 1987, 148; R. V. Bonnert, M. J. Davies,
J. Howarth, P. R. Jenkins, N. J. Lawrence, J.
Chem. Soc. Perkin Trans. 1 1992, 27; A. J.
Wood, P. R. Jenkins, Tetrahedron Lett.,
1997, 38, 1853.
Ph
O
Ph
O
Ph
O
H
HO
H
O
H
O
15, 75%
16, 77%
17, 75%
H
O
OMe
O
O
Ph
O
H
14
H
O
H
O
H
O
OMe
OMe
OMe
O
O
O
b
d
c
Ph
O
Ph
O
Ph
O
[6] A. N. Boa, J. Clark, P. R. Jenkins, N. J.
Lawrence, J. Chem. Soc. Chem. Commun.
1993, 151.
H
O
H
O
H
HO
19, 72%
20, 73%
18, 65%
ˆ
ˆ
Scheme 3. Reagents and conditions: a) H2C CHMgCl, THF, reflux, 2 h; b) NaH, CH2 CHCH2Br,
[7] A. Fürstner, Top. Catal. 1997, 4, 285; S.
Blechert, M. Schuster, Angew. Chem. 1997,
ˆ
THF; c) [RuCl2(CHPh){P(C6H11)3}2] (1), benzene, 608C, 36 h; d) CH2 CHCH2MgCl, THF, 2 h.
Angew. Chem. Int. Ed. 1998, 37, No. 23
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3723-3299 $ 17.50+.50/0
3299

COMMUNICATIONS
109, 2124; Angew. Chem. Int. Ed. Engl. 1997, 36, 2036; R. H. Grubbs,
S. Chang, Tetrahedron 1998, 54, 4413; S. K. Armstrong, J. Chem. Soc.
Perkin Trans 1 1998, 371.
Catalytic Mechanism of the Metal-Free
Hydrogenase from Methanogenic Archaea:
Reversed Stereospecificity of the Catalytic
and Noncatalytic Reaction**
[8] P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew. Chem.
1995, 107, 2179; Angew. Chem. Int. Ed. Engl. 1995, 34, 2039; P. Schwab,
R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 100.
[9] H. S. Overkleeft, U. K. Pandit, Tetrahedron Lett. 1996, 37, 547; M. A.
Leeuwenburgh, H. S. Overkleeft, G. A. van der Marel, J. H. van -
Boom, Synlett 1997, 1263; H. Ovaa, M. A. Leeuwenburgh, H. S.
Overkleeft, G. A. van der Marel, J. H. van Boom, Tetrahedron Lett.
1998, 39, 3025; H. S. Overkleeft, P. Bruggeman, U. K. Pandit,
Tetrahedron Lett. 1988, 39, 3869.
[10] G. Descotes, J. Ramza, J.-M. Basset, S. Pagano, E. Gentil, J. Banoub,
Tetrahedron 1996, 52, 10903.
[11] H. E. Sukkari, J.-P. Gesson, B. Renoux, Tetrahedron Lett. 1998, 39,
4043.
[12] A. Fürstner, T. Muller, J. Org. Chem. 1998, 63, 424.
[13] F. E. Ziegler, Y. Wang, J. Org. Chem. 1998, 63, 426.
[14] P. R. Jenkins, Pure Appl. Chem. 1996, 68, 771.
[15] R. J. Ferrier, C.-K. Lee, T. A. Wood, J. Chem. Soc. Chem Commun.
1991, 690.
[16] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-101536, 101537, 101538, 101539, and 1015340. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
Bernhard H. Geierstanger, Thomas Prasch, Christian
Griesinger,* Gudrun Hartmann, Gerrit Buurman, and
Rolf K. Thauer*
Hydrogenases are enzymes that catalyze reactions with
molecular hydrogen (H2) either as substrate or as product.[1]
They usually contain a redox-active nickel/iron or iron center
that binds and activates H2. Typically hydrogenases also
contain several iron ± sulfur clusters that transfer electrons to
an electron acceptor.[2±4] In addition, most methanogenic
archaea express a metal-free hydrogenase which, therefore,
can neither activate H2 nor catalyze electron transport.[5] All
available evidence indicates that this enzyme activates the
hydrogen acceptor, which then directly reacts with H2.[6]
The metal-free hydrogenase catalyzes the reversible reduc-
tion of N5,N10-methenyl tetrahydromethanopterin (methenyl-
H4MPT, 1) with H2 to N5,N10-methylene tetrahydrometha-
1
nopterin (methylene-H4MPT, 2; DG8' ˆ 5.5 kJmol
;
[17] B. Werschkun, J. Thiem, Angew. Chem. 1997, 109, 2905; Angew. Chem.
Int. Ed. Engl. 1997, 36, 2793.
Scheme 1).[7] This reaction is involved in the reduction of
CO2 with H2 to form CH4 in methanogenic archaea.[8, 9] The
enzyme catalyzes a direct hydride transfer from H2 into the
pro-R position of 2.[10] In addition, the enzyme catalyzes an
exchange of the hydrogen atom in the pro-R position of 2 with
the protons of water,[11] a methenyl-H4MPT-dependent ex-
change of H2 with the solvent,[12, 13] and a methenyl-H4MPT-
dependent ortho/para H2 conversion.[14] These properties of
metal-free hydrogenase are accounted for in the catalytic
mechanism proposed in Scheme 2.[6] The mechanism is based
[18] a) S. J. Miller, S.-H. Kim, Z.-R. Chen, R. H. Grubbs, J. Am. Chem. Soc.
1995, 117, 2108; b) M. S. Visser, N. M. Heron, M. T. Didiuk, J. F. Sagal,
A. H. Hoveyda, J. Am. Chem. Soc. 1996, 118, 4291; c) A. Fürstner, K.
Langemann, J. Org. Chem. 1996, 61, 8746; d) J. S. Clark, J. G. Kettle,
Tetrahedron Lett. 1997, 38, 123; 127.
[19] Studies are underway aimed at improving these poor yields.
[20] a) D. D. Reynolds, W. O. Kenyon, J. Am. Chem. Soc. 1950, 72, 1593; P.
Picard, D. Leclercq, J. Moulines, Tetrahedron Lett. 1975, 2731; P.
Canonne, G. B. Foscolos, D. Belanger, J. Org. Chem. 1980, 45, 1828; E.
Piers, V. G. Ashvinikumar, J. Org. Chem. 1990, 55, 2380; b) D. S.
Middleton, N. S. Simpkins, Tetrahe-
dron Lett. 1988, 29, 1315; c) L. A.
Paquette, J. Tae, J. Org. Chem. 1996,
61, 7860; d) L. A. Paquette, J. T.
Negri, J. Am. Chem. Soc. 1991, 113,
pro-S
Ha
5072.
H
[21] After submission of this paper
publication appeared on the spiroan-
nulation of different set of
a
pro-R
H2-forming
methylene tetrahydromethanopterin
dehydrogenase
N
N
O
N
14a
O
Hb
14a
+
a
N
H
N
H
CH3
CH3
N
N
sugar derivatives by RCM: P. A. V.
van Hooft, M. A. Leeuvwenburgh,
H. S. Overkleeft, G. A. ven der
Marel, C. A. A. van Boeckel, J. H.
van Boom, Tetrahedron Lett. 1998,
39, 6061
+
H2
+
H+
H
H
∆G0' = – 5.5 kJ mol–1
CH3
N
H
CH3
N
N
H
H2N
H2N
1
2
[22] A. Rosenthal, P. Catsoulacos, Can. J.
Chem. 1969, 47, 2747.
Scheme 1. The reaction catalyzed by the metal-free hydrogenase. For complete structures of 1 and 2 including
sidechains, see references [5, 10].
[*] Prof. Dr. C. Griesinger, Dr. B. H. Geierstanger, Dr. T. Prasch
Institut für Organische Chemie der Universität
Marie-Curie-Strasse 11, D-60439 Frankfurt am Main (Germany)
Fax: (‡49)69-7982-9128
E-mail: cigr@org.chemie.uni-frankfurt.de
Prof. Dr. R. K. Thauer, Dr. G. Hartmann, G. Buurman
Max-Planck-Institut für terrestrische Mikrobiologie
Karl-von-Frisch-Strasse, D-35043 Marburg (Germany)
Fax: (‡49)6421-178209
E-mail: thauer@mailer.uni-marburg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 472P4).
3300
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3723-3300 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 23