Synthesis of fused cyclic systems containing medium-sized rings through tandem ROM-RCM of norbornene derivatives embedded in a carbohydrate template

Article abstract of DOI:10.1021/jo802077t

A general approach for the synthesis of fused cyclic systems containing medium-sized rings (7-9) has been developed. The key steps involve a diastereoface-selective Diels-Alder reaction of the dienophiles 4a-d attached to a furanosugar with cyclopentadiene and ring opening (ROM)-ring closing metathesis (RCM) of the resulting norbornene derivatives 10a-d and 11a-d. Diels-Alder reaction of the dienophiles 4a-d with cyclopentadiene in the absence of a catalyst produced 10a-d as the major product arising through addition of the diene to the unhindered Si-face. The most interesting and new aspect of the Diels-Alder reaction of these dienophiles is the accessibility of the Re-face that was blocked by the alkenyl chains under Lewis acid catalysis producing the diastereoisomers 11a-d exclusively. The reversal of facial selectivity from an uncatalyzed reaction to a catalyzed one is unprecedented. The observed stereochemical dichotomy is attributed to rotation of the enone moiety along the o bond linking the sugar moiety during formation of the chelate 13. This makes the Re-face of the enone moiety in 4a-d unhindered. Diels-Alder reaction of the carbocyelic analogue 15 under Lewis acid catalysis produced a 1:1 mixture of the adducts 16 and 17 confirming the participation of sugar ring oxygen in chelate formation. Finally ROM-RCM of 10a-d and 11a-d with Grubbs' catalyst afforded the cis-syn-cis and cis-anti-cis bicyclo-annulated sugars 21a-d and 23a-d, respectively, containing 7-9 membered rings.

Full text of DOI:10.1021/jo802077t

Synthesis of Fused Cyclic Systems Containing Medium-Sized Rings
through Tandem ROM-RCM of Norbornene Derivatives Embedded
in a Carbohydrate Template
Chanchal K. Malik,† Ram Naresh Yadav,† Michael G. B. Drew,‡ and Subrata Ghosh*,†
Department of Organic Chemistry, Indian Association for the CultiVation of Science, JadaVpur,
Kolkata 700032, India, and Department of Chemistry, The UniVersity of Reading, Whiteknights, Reading
RG6 6AD, United Kingdom
ocsg@iacs.res.in
ReceiVed September 19, 2008
A general approach for the synthesis of fused cyclic systems containing medium-sized rings (7-9) has
been developed. The key steps involve a diastereoface-selective Diels-Alder reaction of the dienophiles
4a-d attached to a furanosugar with cyclopentadiene and ring opening (ROM)-ring closing metathesis
(RCM) of the resulting norbornene derivatives 10a-d and 11a-d. Diels-Alder reaction of the dienophiles
4a-d with cyclopentadiene in the absence of a catalyst produced 10a-d as the major product arising
through addition of the diene to the unhindered Si-face. The most interesting and new aspect of the
Diels-Alder reaction of these dienophiles is the accessibility of the Re-face that was blocked by the
alkenyl chains under Lewis acid catalysis producing the diastereoisomers 11a-d exclusively. The reversal
of facial selectivity from an uncatalyzed reaction to a catalyzed one is unprecedented. The observed
stereochemical dichotomy is attributed to rotation of the enone moiety along the σ bond linking the
sugar moiety during formation of the chelate 13. This makes the Re-face of the enone moiety in 4a-d
unhindered. Diels-Alder reaction of the carbocyclic analogue 15 under Lewis acid catalysis produced a
1:1 mixture of the adducts 16 and 17 confirming the participation of sugar ring oxygen in chelate formation.
Finally ROM-RCM of 10a-d and 11a-d with Grubbs’ catalyst afforded the cis-syn-cis and cis-anti-cis
bicyclo-annulated sugars 21a-d and 23a-d, respectively, containing 7-9 membered rings.
Introduction
A number of strategies involving intramolecular [4+2],2 [4+3],3
and [4+4]4 cycloaddition reactions have been reported for direct
Fused bi- and tricyclic systems containing medium sized rings
(7-9) are frequently encountered in biologically active natural
products. Development of new synthetic approaches to these
ring systems thus continues to be an important goal in organic
synthesis. Toward this endeavor a number of elegant strategies
have been developed.1 Annulation of medium rings onto a pre-
existing ring is generally employed for this purpose. However,
a single-step method for the direct construction of these systems
is especially attractive due to its brevity and diastereoselectivity.
(1) For reviews on the synthesis of eight-membered carbocycles see: (a)
Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (b) Mehta, G.; Sing,
V. Chem. ReV. 1999, 99, 881. (c) Michant, A.; Rodriguez, J. Angew. Chem.,
Int. Ed. 2006, 45, 5740. (d) Lopez, F.; Mascarenas, J. L. Chem. Eur. J. 2007,
13, 2172.
(2) Sakan, K.; Smith, D. A. Tetrahedron Lett. 1984, 25, 2081.
(3) For a review on [4+3] cycloaddition reaction see: (a) Harmata, M. Acc.
Chem. Res. 2001, 34, 595. For some recent works see: (b) Harmata, M.; Ghosh,
S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003,
125, 2058. (c) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem.
Soc. 2003, 125, 12694. (d) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed,
J. W. J. Org. Chem. 2003, 68, 7899. (e) Rameshkumar, C.; Hsung, R. P.
Angew. Chem., Int. Ed. 2004, 43, 615. (f) Huang, J.; Hsung, R. P. J. Am. Chem.
Soc. 2005, 127, 50. (g) Craft, D. T.; Gung, B. W. Tetrahedron Lett. 2008, 49,
5931.
* Corresponding author. Fax: (+) 91 33 2473 2805. Phone:(+) 91 33 2473
4971.
† Indian Association for the Cultivation of Science.
‡ The University of Reading.
10.1021/jo802077t CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1957–1963 1957

Malik et al.
SCHEME 1. Synthesis of Dienophiles 4a-e
construction of fused cyclic systems with either seven- or eight-
membered rings only.
Since the pioneering work from the groups of Grubbs and
Schrock, RCM5reaction of dienes and enynes has emerged as a
powerful tool for the synthesis of rings of different sizes,
especially medium-sized rings which are difficult to make by
other methods. For example, a tandem RCM of dienynes has
been employed for the synthesis of fused bicycles containing
seven-membered6 as well as eight-membered7 rings. Another
metathesis-based strategy developed by Grubbs and co-workers8
to construct fused bicycles involves a tandem ROM-RCM of
appropriately constructed bicyclo[2.2.1]heptenes. Subsequent to
this observation, there are reports of the synthesis of fused
bicycles with common rings using tandem ROM-RCM of
norbornene derivatives along with its application in natural
products synthesis.9 However, ROM-RCM of norbornene
derivatives to construct fused bicycles with medium-sized rings
is relatively less explored and restricted to the synthesis of
structurally simple systems with seven- and eight-membered
rings only.10 Synthesis of nine-membered carbocyclic rings
through RCM is difficult to achieve and to date there is only
one successful attempt.11
invoked. The required dienophiles were prepared from D-
glucofuranose derivative 1 as illustrated by the synthesis of 4a
(Scheme 1).
In connection to our interest12 in the synthesis of chiral target
molecules from carbohydrates, we initiated an investigation on
ROM-RCM of norbornene derivatives embedded in a furano-
sugar with the following objectives: to determine the influence
of an intervening sugar unit on the efficiency of ROM-RCM
and to develop a strategy for the synthesis of chirally pure fused
cyclic systems with seven-, eight-, and nine-membered rings.
The results of this investigation are presented here.
Addition of vinyl magnesium bromide to the ketone 113
followed by protection of the resulting carbinol gave the benzyl
ether 2a. The 5,6-isopropylidine unit in 2a was selectively
removed by treatment with aqueous acetic acid at room
temperature. Periodate cleavage of the resulting diol gave the
aldehyde 3a. Addition of vinyl magnesium bromide to the
aldehyde 3a followed by Dess-Martin periodinane (DMP)
oxidation afforded the enone 4a in excellent yield. In a similar
fashion the dienophiles 4b-d were prepared by addition of
appropriate alkenyl magnesium halides to the ketone 1. The
same protocol was used to prepare the dienophile 4e from the
compound 2e.
Results and Discussion
To incorporate a sugar unit with an alkene chain into
norbornene derivatives required for investigating ROM-RCM,
Diels-Alder reaction of dienophiles 4 with cyclopentadiene was
Reaction of dienophiles 4 with cyclopentadiene is expected
to give rise to four diastereoisomers arising through the endo
and exo mode of addition from Re and Si faces. In connection
to asymmetric Diels-Alder reaction, it was demonstrated14 that
face discrimination could be achieved by blocking one face of
the enone by a bulky substituent. In the dienophiles 4 the front
face (Re-face) is blocked by a syn alkyl substituent (R) on the
center next to the side chain bearing the enone unit. Thus, it is
expected that dienes will add to the dienophiles 4 preferentially
from the unhindered Si-face. Except for a few reports15 on
Diels-Alder reaction of acrylates derived from carbohydrates
as removable chiral auxiliaries, there is hardly any investiga-
tion16 on Diels-Alder reaction of dienophiles related to 4.
To determine the facial selectivity, the dienophiles 4 were
initially subjected to Diels-Alder reaction with 2,3-dimethylb-
utadiene (DMB) (Scheme 2). This eliminates the possibility of
formation of regio- and endo/exo isomers. Cycloaddition was
carried out by heating a solution of the enones in toluene with
(4) (a) Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678. (b)
Sieburth, S. M.; Chen, J. J. Am. Chem. Soc. 1991, 113, 8163. (c) Wender, P. A.;
Nuss, J. M.; Smith, D. B.; Sua´rez-Sobrino, A.; Vågberg, J.; Decosta, D.; Bordner,
J. J. Org. Chem. 1997, 62, 4908. (d) Sieburth, S. M.; McGee, K. F.; Al-Tel,
T. H. J. Am. Chem. Soc. 1998, 120, 587. (e) Sieburth, S. M.; McGee, K. F., Jr.;
Al-Tel, T. H. Tetrahedron Lett. 1999, 40, 4007. (f) Sieburth, S. M.; Madsen-
Duggan, C. B.; Zhang, F. Tetrahedron Lett. 2001, 42, 5155. (g) Li, L.; Chase,
C. E.; West, F. G. Chem. Commun. 2008, 4025.
(5) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446. (b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036. (c)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (d) Armstrong, S. K.;
J. Chem. Soc., Perkin Trans. 1 1998, 371. (e) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012. (f) Deiters, A.; Martin, S. Chem. ReV. 2004, 2199. (g)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44,
4490. (h) Ghosh, S.; Ghosh, S.; Sarkar, N. J. Chem. Sci. 2006, 118, 223.
(6) Kim, S. H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem.
1996, 61, 1073.
(7) Boyer, F. D.; Hanna, I.; Ricard, L. Org. Lett. 2001, 3, 3095.
(8) (a) Stille, J. R.; Santarsiero, B. D.; Grubbs, R. H. J. Org. Chem. 1990,
55, 843.
(9) (a) Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828. (b) Hagiwara, H.; Katsumi,
T.; Endou, S.; Hoshi, T.; Suzuki, T. Tetrahedron 2002, 58, 6651. (c) Wrobleski,
A.; Sahasrabudhe, K.; Aube, J. J. Am. Chem. Soc. 2004, 126, 5475. (d)
Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5805. (e) Holtsclaw, J.; Koreeda, M. Org. Lett.
2004, 6, 3719. (f) Hart, A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128,
1094. (g) Maechling, S.; Norman, S. E.; Mckendrick, J. E.; Basra, S.; Koppner,
K.; Blechert, S. Tetrahedron Lett. 2006, 47, 189. (h) Maity, S.; Ghosh, S.
Tetrahedron Lett. 2008, 49, 1133.
(10) (a) Stragies, R.; Blechert, S. Synlett, 1998, 169. (b) Malik, C. K.; Ghosh,
S. Org. Lett. 2007, 9, 2537.
(11) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89.
(12) Banerjee, S.; Ghosh, S. J. Org. Chem. 2003, 68, 3981.
(13) Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593.
(14) (a) Helmchen, G.; Schmierer, R. Angew. Chem., Int. Ed. 1981, 20, 205.
(b) Oppolzer, W.; Chapuis, C.; Dao, G. M.; Reichlin, D.; Godel, T. Tetrahedron
Lett. 1982, 23, 4781. (c) Choy, W.; Reed, L. A., III; Masamune, S. J. Org.
Chem. 1983, 48, 1137. (d) Masamune, S.; Reed, L. A., III; Davis, J. T.; Choy,
W. J. Org. Chem. 1983, 48, 4441. (e) Oppolzer, W.; Chapuis, C.; Bernardinelli,
G. HelV. Chim. Acta 1984, 67, 1397. (f) Evans, D. A.; Chapman, K. T.; Bisaha,
J. J. Am. Chem. Soc. 1984, 106, 4261.
(15) Hultin, P. G.; Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53,
14823.
(16) Ferrier, J.; Middleton, S. Chem. ReV. 1993, 93, 2779.
1958 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of Fused Cyclic Systems
SCHEME 2. Diels-Alder Reaction of 4 with DMB
SCHEME 3. Diels-Alder Reaction of 4 with C5H6
TABLE 2. Diels-Alder Reaction of Enones 4 with
Cyclopentadiene
entry
1
dienophile
products
yeild (diastereomeric ratio)
4a
10a + 11a
88% (3:1)a
84% (1:100)b
89% (4:1)a
2
3
4
4b
4c
4d
10b + 11b
10c + 11c
10d + 11d
86% (1:100)b
89% (4:1)a
87% (1:100)b
90% (16:1)a
88% (1:100)b
a THF, 0 °C. b ZnCl2, DCM, -78 °C.
which the carboxylic acid S-(-)-9 was derived possesses the
structure 6a. In a similar fashion the inseparable mixture (ca.
2:1) of adducts 5a and 6a obtained under noncatalyzed condition
was degraded through the mixture of diols 7 and 8 to provide
the R-(+)-carboxylic acid 9, [R]26D + 30 (c 0.0158, EtOH). The
sign of the specific rotation of the carboxylic acid establishes
the structure of the major adduct in the mixture as 5a. The
magnitude of the specific rotation observed for R-(+)-9 when
compared with that reported for S-(-)-9 is in conformity with
about a 2:1 ratio of the adducts 5a and 6a obtained in the
noncatalyzed reaction. Structures of adducts 5b-e and 6b-e
were based on analogy to the formation of compounds 5a and
6a from Diels-Alder reaction of the dienophile 4a with DMB.
Diels-Alder reaction of the dienophiles 4a-d with cyclo-
pentadiene was then investigated (Scheme 3). The results are
summarized in Table 2. Unlike the reaction with DMB, with
cyclopentadiene an improved diastereoface selectivity was
observed in all cases. No exoadduct was formed. The dienophile
4a on reaction with cyclopentadiene in THF at 0 °C afforded a
mixture of the endoadducts 10a and 11a in 3:1 ratio (entry 1,
condition “a”). With a longer alkenyl chain such as allyl and
homoallyl (entries 2 and 3), the ratio of the diastereoisomeric
products increased to 4:1. However, a Me substituent on the
alkene unit dramatically increased the ratio of products 10d and
11d to 16:1 (entry 4). The structure of the major adduct 10d
was determined through single crystal X-ray.18
TABLE 1. Diels-Alder Reaction of Enones 4 with DMB
entry
1
dienophile
products
yeild (diastereomeric ratio)
4a
5a + 6a
83% (2:1)a
81% (1:100)b
85% (2:1)a
80% (1:100)b
88% (2:1)a
78% (1:100)b
86% (6:1)a
82% (1:100)b
80% (1:1)a
87% (1:1)b
2
3
4
5
4b
4c
4d
4e
5b + 6b
5c + 6c
5d + 6d
5e + 6e
a Toluene, 120 °C. b ZnCl2, DCM, -20 °C to rt.
DMB in a sealed tube at 120 °C. The results are summarized
in Table 1. The enone 4a afforded a mixture of adducts 5a and
6a in 83% yield in a ratio of 2:1 (entry 1).
Increasing the chain length of the substituent “R” from vinyl
to allyl or homoallyl did not have any effect on the stereo-
chemical outcome. The enones 4b and 4c gave the diastereoi-
someric pairs 5b, 6b and 5c, 6c, respectively, in almost similar
ratios (2:1) (entries 2 and 3). However, a significant increase in
the ratio (6:1) of the diastereoisomers 5d and 6d (entry 4) was
observed on replacing vinyl or allyl in the dienophile 4 by a
branched alkene such as methallyl demonstrating that increasing
bulk of the substituent has a significant effect in diastereoface
selection. Structural assignment to these adducts followed from
the following transformations. The adduct 6a, obtained exclu-
sively from the ZnCl2 catalyzed reaction of the dienophile 4a
with DMB (vide infra), was treated with acetic acid containing
a catalytic amount of HCl to provide an anomeric mixture of
the diols 8 in 70% yield. Treatment of the mixture of these
diols with periodic acid afforded in 56% yield the known17
carboxylic acid S-(-)-9, [R]25D - 81.4 (c 0.0153, EtOH) [lit.17
Thus the minor adduct obtained in the reaction of 4d was
assigned structure 11d. The major and minor adducts from
Diels-Alder reaction of 4a-c were assigned structures 10a-c
and 11a-c, respectively, in analogy to the formation of 10d
and 11d from 4d. The X-ray structure of adduct 10d revealed
(17) Akkari, R.; Calme`s, M.; Escale, F.; Iapichella, J.; Rolland, M.; Martinez,
J. Tetrahedron: Asymmetry 2004, 15, 2515.
(18) Crystallographic data for compound 10d have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication no. CCDC
680372. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223-336033.
E-mail: deposit@ccdc.cam.ac.uk.
[R]25 -85 (c 1.8, EtOH) (ee 99%)]. Thus the adduct from
D
J. Org. Chem. Vol. 74, No. 5, 2009 1959

Malik et al.
SCHEME 4. Synthesis and Diels-Alder Reaction of 15
that cyclopentadiene added to the unhindered Si-face of dieno-
phile 4d through s-cis conformation of the enone as depicted
in structure 4.
Lewis acid catalysts have profound influence on diastereoface
discrimination in the Diels-Alder reaction through formation
of a chelate that rigidly holds the enone moiety with one face
shielded by a neighboring substituent.14 Improved diastereose-
lectivities were observed in such cases compared to the
noncatalyzed reactions resulting in the formation of one
diastereoisomer predominantly. However, this approach fails to
provide the diastereoisomer arising by addition of the diene to
the face blocked by the substituent. Helmchen and co-workers19
and later on Waldmann20 demonstrated that both diastereomeric
adducts could be obtained depending on the nature of the Lewis
acid employed in the Diels-Alder reaction of acrylates/
acrylamides with appropriately designed chiral auxiliaries. A
Lewis acid capable of undergoing chelation with a neighboring
heteroatom in the auxiliary forms a rigidly held complex. This
complex shields one face of the enone and produces one
diasteroisomer predominantly. On the other hand, a Lewis acid
incapable of chelation produces the other diastereoisomer. In
these examples the coordinated Lewis acid itself blocks one
face and the substituent at the chiral center in the auxiliary makes
no significant contribution to the diastereoface differentiation.19
In light of the above observations, we became interested in
investigating the Lewis acid catalyzed Diels-Alder reaction of
the dienophiles 4 in order to explore the influence of Lewis
acid on the stereochemical outcome. We visualized that the σ
bond linking the enone moiety in the Lewis acid (MXn)-
complexed dienophile 12 would rotate due to increased eclipsing
interaction with the substituent R and undergo chelation with
the sugar ring oxygen to form a rigid bidentate chelate complex
13. In this complex the Si-face is blocked by the substituent
“R”. Addition is then expected to take place on the Re-face
eventually resulting in reversal of facial selectivity. Gratifyingly,
the facial selectivity in the Diels-Alder reaction of the
dienophiles 4a-d could be reversed with Lewis acid. After
considerable experimentation with a number of Lewis acids,
ZnCl2 turned out to be the best catalyst in reversing the facial
selectivity. Thus reaction of enones 4a-d with DMB in toluene
at 0 °C in the presence of ZnCl2 afforded almost exclusively
adducts 6a-d (Table 1). Similarly reaction of 4a-d with
cyclopentadiene in the presence of ZnCl2 gave exclusively
adducts 11a-d (Table 2, condition “b”), respectively. Thus
under noncatalyzed condition dienes added preferentially to the
Si-face as the Re-face was blocked by the substituent “R” while
with the ZnCl2, reaction presumably proceeded through the
chelated complex 13 (M ) Zn) in which the Si-face was blocked
by “R”. The Lewis acid in these examples is simply changing
the orientation of the Re-face of the enone from hindered to
unhindered through rotation during formation of the chelate.
of sugar ring oxygen in metal chelate formation in the
Diels-Alder reaction of dienophiles attached to the sugar unit
resulting in reversal of facial selectivity is unprecedented.
To understand the role of sugar ring oxygen in reversing the
face selectivity, the Diels-Alder reaction of the carbocyclic
analogue 15 was investigated. The dienophile 15 was prepared
from the aldehyde 1421 by addition of vinyl magnesium bromide
followed by oxidation of the resulting carbinol (Scheme 4).
As expected, reaction with cyclopentadiene without catalyst
gave an inseparable mixture of adducts 16 and 17 in 2.8:1 ratio.
With AlCl3 or ZnCl2 the same products were formed in ca. 1:1
ratio. This investigation clearly demonstrates that the ring
oxygen in the carbohydrate unit in dienophiles 4 was involved
in reversing the selectivity in the ZnCl2 catalyzed Diels-Alder
reaction. Thus the sugar moiety in dienophiles 4, under
noncatalyzed and catalyzed conditions, led the enone unit to
adopt two different orientations so as to expose either the Si-
face or the Re-face selectively for Diels-Alder addition.
ROM-RCM of the bicyclo[2.2.1]heptene derivatives was next
investigated (Scheme 5). Treatment of compound 10a in
dichloromethane in the presence of catalyst 18 under ethylene
atmosphere led to complete disappearance of the starting
material within 1 h. The product obtained in 92% yield was
characterized as ring-opened product 20a. Attempted ROM-
RCM of 10a under identical conditions with the more reactive
catalyst 19 caused extensive polymerization of the norbornene
derivatives.
However, when ring-opened product 20a was treated with
catalyst 19, smooth ring closure took place in 6 h to produce
oxa-tricycle 21a in 86% yield. On the basis of the above
observation, the following protocol was used to accomplish
ROM-RCM. The norbornene derivatives were first treated with
catalyst 18 until the disappearance of the starting materials
(1-1.5 h) (TLC). At this stage, in each case except 10c and
11b, analysis of an aliquot of the reaction mixture showed the
presence of the ROM products 20a,b,d and 22a,c,d only. To
this reaction mixture catalyst 19 was then added and the reaction
was continued until the ROM product disappeared. In this way
the norbornene derivatives 10a,b,d and 11a,c,d afforded re-
spectively the bicyclo-annulated products 21a,b,d and 23a,c,d
in very good yields. Compounds 10c and 11b gave directly the
(19) (a) Poll, T.; Helmchen, G.; Bauer, B. Tetrahedron Lett. 1984, 25, 2191.
(b) Poll, T.; Sobczak, A.; Hartman, H.; Helmchen, G. Tetrahedron Lett. 1985,
26, 3095. (c) Poll, T.; Metter, J. O.; Helmchen, G. Angew. Chem., Int. Ed. 1985,
24, 112.
(20) Waldmann, H. J. Org. Chem. 1988, 53, 6133.
(21) Stevens, A. T.; Bull, J. R.; Chibale, K. Org. Biomol. Chem. 2008, 6,
586.
That the substituent “R” is responsible for face discrimination
under both catalyzed and noncatalyzed reactions is demonstrated
by reaction of the enone 4e with DMB to produce a 1:1 mixture
of the adducts 5e and 6e under both conditions. Involvement
1960 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of Fused Cyclic Systems
SCHEME 5. ROM-RCM of Norbornene Derivatives 10 and 11
SCHEME 6. ROM-RCM of 16 and 17
is the construction of both cis-syn-cis and cis-anti-cis bicyclo-
annulated sugars. The bicyclo-annulated sugars thus obtained
will be of considerable synthetic potential as the carbohydrate
ring can either be converted to a carbocycle16 to produce linearly
fused tricyclic systems or cleaved24 to afford fused bicyclic
systems.
Experimental Section
nine-membered and eight-membered carbocyclic derivatives 21c
and 23b, respectively, in 1 h with catalyst 18. The structures of
products 21a and 23a were ascertained through analysis of their
NMR (1H, 13C, and NOESY) spectra.
Diels-Ader Reactions of Dienophile 4a with DMB.
((3aR,5S,6S,6aR)-6-(Benzyloxy)tetrahydro-2,2-dimethyl-6-vinyl-
furo[2,3-d][1,3]dioxol-5-yl)((S)-3,4-dimethylcyclohex-3-enyl)meth-
anone (5a). A mixture of the dienophile 4a (70 mg, 0.21 mmol),
DMB (0.1 mL, 0.89 mmol), and a catalytic amount of hydroquinone
in toluene (2 mL) was heated at 120 °C for 3 h in a sealed tube.
The solvent was evaporated under reduced pressure to afford an
inseparable mixture of cycloadducts 5a and 6a (72 mg, 83%) in
After successfully accomplishing ROM-RCM of the nor-
bornene derivatives to construct fused oxa-tricycles, we became
interested in exploring the reactivity of 16 and 17 which do not
have an oxygen atom in the neighboring ring. Under the above
reaction condition, the inseparable mixture of adducts 16 and
17 afforded the cis-syn-cis and cis-anti-cis 5-7-6 tricycles 24
and 25 in 60% and 26% isolated yields, respectively (Scheme
6). Direct synthesis of 5-7-6 tricyclic systems is of great
significance as this unit represents the core structure of a number
of highly biologically active natural products.22
In conclusion, we have demonstrated that the carbohydrate
ring when attached to an acyclic dienophile, under appropriate
reaction condition, can direct addition of dienes either to the
Si-face or to the Re-face enabling synthesis of both diastereoi-
someric adducts. This face-selective Diels-Alder reaction of
the dienophiles with cyclopentadiene in combination with ROM-
RCM of the resulting norbornene derivatives offers a general
expedient approach for the synthesis of densely functionalized
bicyclo-annulated sugars with seven-, eight-, and nine-mem-
bered23 rings. The most notable feature of the present protocol
2:1 ratio (by NMR), [R]25 + 61.3 (c 7.8, CHCl3); IR νmax 1718
D
1
cm-1; H NMR (of the mixture) δ 1.40 (3H, s), 1.45-1.54 (1H,
m), 1.59 (6H, s), 1.62 (3H, s), 1.81-2.09 (4H, m), 2.18-2.27 (1H,
m), 2.95-3.05 (1H, m), 4.62-4.68 (2H, m), 4.74-4.77 (1H, m),
4.92-4.99 (1H, m), 5.31 (1H, d, J ) 17.7 Hz), 5.42 (1H, d, J )
11.2 Hz), 5.63-5.74 (1H, m), 5.97 (1H, d, J ) 3.3 Hz), 7.27-7.39
(5H, m); 13C NMR (for the major isomer 5a from the mixture) δ
18.9 (CH3), 19.1 (CH3), 26.5 (CH2), 26.7 (CH3), 27.1 (CH3), 31.5
(CH2), 32.2 (CH2), 44.8 (CH), 67.3 (CH2), 81.4 (CH), 84.9 (CH),
86.1 (C), 104.4 (CH), 113.4 (C), 119.3 (CH2), 124.2 (C), 124.9
(C), 127.01 (CH), 127.5 (CH), 128.3 (CH), 133.7 (CH), 138.3 (C),
208.7 (CO); HRMS (ESI) m/z (M + Na)+ calcd for C25H32O5Na
435.2148, found 435.2140.
Diels-Alder Reaction of Dienophile 4a with Cyclopentadi-
ene. ((3aR,5S,6S,6aR)-6-(Benzyloxy)dihydro-2,2-dimethyl-6-
vinyl-5H-furo[3,2-ol][1,3]dioxol-5-yl)(bicyclo[2.2.1]hept-5-en-
2yl)methanone (10a) and ((3aR,5S,6S,6aR)-6-(Benzyloxy)dihydro-
2,2-dimethyl-6-vinyl-5H-furo[3,2-d][1,3]dioxol-5yl)(bicyclo[2.2.1]hept-
5-en-2yl)methanone (11a). To a stirred solution of dienophile 4a
(22) For selected synthesis of 5-7-6 tricyclic ring systems see: (a) Paquette,
L. A.; Lin, H. S.; Belmont, D. T.; Springer, J. P. J. Org. Chem. 1986, 51, 4807.
(b) Piers, E.; Frissen, R. W. J. Org. Chem. 1986, 51, 3405. (c) Mehta, G.;
Krishnamurthy, N.; Karra, S. R. J. Am. Chem. Soc. 1991, 113, 5765. (d) Lin, S.;
Dudley, G. B.; Tan, D. S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
2188. (e) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030.
(f) Mehta, G.; Pallavi, K.; Umarye, J. D. Chem. Commun. 2005, 35, 4456.
(23) For synthetic approaches to natural products containing 5-9 membered
ring systems see: (a) Paquette, L. A.; Edmondson, S. D.; Monck, N.; Rogers,
R. D. J. Org. Chem. 1999, 64, 3255. (b) Paquette, L. A.; Yang, J.; Long, Y. O.
J. Am. Chem. Soc. 2002, 124, 6542. (c) Yang, J.; Long, Y. O.; Paquette, L. A.
J. Am. Chem. Soc. 2003, 125, 1567.
(24) Cf.: Haque, A.; Panda, J.; Ghosh, S. Indian J. Chem. 1999, 38B, 8.
J. Org. Chem. Vol. 74, No. 5, 2009 1961

Malik et al.
(100 mg, 0.30 mmol) in dry THF (3 mL) at 0 °C was added freshly
distilled cyclopentadiene (140 mg, 3.03 mmol) dropwise. Stirring
was continued for 1 h at 0 °C and 5 h at rt. Solvent was removed
in vacuo and the residue was purified by column chromatography
to afford the cycloadduct 10a (75 mg, 62%) and 11a (30 mg, 26%).
purging ethylene through it. After 30 min the catalyst 18 (15 mg,
0.018 mmol, 7 mol%) was added and stirring was continued. After
1 h TLC of the reaction mixture indicated complete disappearance
of the starting material. Removal of solvent from an aliquot of the
reaction mixture revealed it to be the ring opened product 20a only
(6 mg): [R]24D +28.4 (c 1.8, CHCl3); IR νmax 1710 cm-1; 1H NMR
δ 1.44-1.47 (1H, m), 1.36 (3H, s), 1.57 (3H, s), 1.76-1.83 (2H,
m), 1.91-2.02 (1H, m), 2.43-2.57 (1H, m), 2.93-3.05 (1H, m),
3.48-3.57 (1H, m), 4.52 (1H, s), 4.58-4.69 (3H, m), 4.87-4.93
(2H, m), 5.01 (2H, d, J ) 17.0 Hz), 5.32 (1H, d, J ) 17.8 Hz),
5.38 (1H, d, J ) 11.3 Hz), 5.67 (3H, m), 5.93 (1H, d, J ) 3.3 Hz),
7.25-7.42 (5H, m); 13C NMR δ 26.9 (CH3), 27.1 (CH3), 34.1 (CH2),
39.2 (CH2), 43.7 (CH), 46.1 (CH), 52.3 (CH), 67.1 (CH2), 81.5
(CH), 85.7 (CH), 85.9 (C), 104.4 (CH), 113.3 (C), 113.4 (CH2),
114.9 (CH2), 119.5 (CH2), 127.3 (CH), 127.4 (CH), 128.3 (CH),
134.4 (CH), 138.4 (C), 139.8 (CH), 141.9 (CH), 209.0 (CO); HRMS
(ESI) m/z (M + Na)+ calcd for C26H32O5Na 447.2147, found
447.2145. Catalyst 19 (6 mg, 0.007mmol, 2.8 mol %) was then
added to the mixture and stirring was continued for 6 h (TLC) under
ethylene atmosphere. The solvent was removed under vacuum. The
residual mass was purified by column chromatography to afford
10a: colorless liquid, [R]26 +74.0 (c 1.75, CHCl3); IR νmax 1720
D
1
cm-1; H NMR δ 1.25 (1H, d, J ) 7.8 Hz), 1.32-1.36 (2H, m),
1.39 (3H, s), 1.61 (3H, s), 1.74-1.82 (1H, m), 2.86 (1H, br s),
3.67 (1H, br s), 3.29-3.32 (1H, m), 4.60-4.73 (4H, m), 5.30 (1H,
d, J ) 17.8 Hz), 5.42 (1H, d, J ) 11.3 Hz), 5.73 (1H, dd, J )
11.4, 17.7 Hz), 5.87 (1H, dd, J ) 2.9, 5.3 Hz), 5.96 (1H, d, J )
3.4 Hz), 6.11 (1H, dd, J ) 2.9, 5.4 Hz), 7.28-7.41 (5H, m); 13C
NMR δ 26.8 (CH3), 27.1 (CH3), 29.1 (CH2), 42.8 (CH), 45.7 (CH),
49.2 (CH), 49.9 (CH2), 67.3 (CH2), 81.5 (CH), 85.7 (CH), 86.0
(C), 104.5 (CH), 113.4 (C), 119.3 (CH2), 127.1 (CH), 127.5 (CH),
128.4 (CH), 132.5 (CH), 134.2 (CH), 137.1 (CH), 138.5 (C), 207.2
(CO); HRMS (ESI) m/z (M + Na)+ calcd for C24H28O5Na 419.1834,
found 419.1838. 11a: [R]26 +22.0 (c 1.8, CHCl3); IR νmax 1710
D
cm-1; 1H NMR δ 1.27 (1H, d, J ) 7.7 Hz), 1.41 (4H, s), 1.50-1.56
(1H, m), 1.64 (3H, s), 1.67-1.69 (1H, m), 2.88 (1H, br s), 3.31
(1H, br s), 3.34-3.37 (1H. m), 4.67 (2H, d, J ) 11.5 Hz),
4.79 (1H, d, J ) 11.3 Hz), 4.96 (1H, s), 5.31 (1H, d, J ) 17.7 Hz),
5.40 (1H, d, J ) 11.2 Hz), 5.66 (1H, dd, J ) 11.2, 17.6 Hz), 5.80
(1H, dd, J ) 2.4, 5.4 Hz), 5.95 (1H, d, J ) 3.3 Hz), 6.17 (1H, dd,
J ) 3, 5.4 Hz), 7.29-7.42 (5H, m); 13C NMR δ 26.8 (CH3), 27.2
(CH3), 27.6 (CH2), 42.9 (CH), 47.2 (CH), 48.9 (CH), 50.3 (CH2),
67.3 (CH2), 81.4 (CH), 85.4 (CH), 86.1 (C), 104.3 (CH), 113.3
(C), 119.2 (CH2), 126.9 (CH), 127.6 (CH), 128.4 (CH), 130.9 (CH),
133.6 (CH), 138.1 (CH), 138.4 (C), 204.9 (CO); HRMS (ESI) m/z
(M + Na)+ calcd for C24H28O5Na 419.1834, found 419.1837.
Lewis Acid Catalyzed Diels-Alder Reactions of Dienophile
4a with DMB. ((3aR,5S,6S,6aR)-6-(Benzyloxy)tetrahydro-2,2-
dimethyl-6-vinylfuro[2,3-d][1,3]dioxol-5-yl)((R)-3,4-dimethylcy-
clohex-3-enyl)methanone (6a). To a magnetically stirred solution
of the dienophile 4a (60 mg, 0.18 mmol) in DCM (4 mL) at -20
°C was added ZnCl2 (47 mg, 0.34 mmol) then the mixture was
stirred for 15 min followed by addition of DMB (0.05 mL, 0.44
mmol). After being stirred for an additional 1 h, the reaction mixture
was allowed to attain rt and quenched with brine (0.5 mL) then
worked up in the usual way to afford after column chromatography
the adduct 6a (62 mg, 83%): [R]25D +34.3 (c 6.2, CHCl3); IR νmax
compound 21a (86 mg, 86%): [R]24 -27.5 (c 1.5, CHCl3); IR
D
ν
max 1726 cm-1; 1H NMR δ 1.22-1.36 (1H, m), 1.40 (3H, s), 1.60
(3H, s), 1.72-1.76 (1H, m), 1.93-1.97 (1H, m), 2.13-2.19 (1H,
m), 2.39-2.49 (1H, m), 3.01-3.11 (1H, m), 3.73-3.79 (1H, m),
4.52 (1H, d, J ) 10.3 Hz), 4.59 (1H, d, J ) 10.3 Hz), 4.64 (1H, d,
J ) 3.5 Hz), 4.87 (1H, s), 4.94 (1H, d, J ) 10.3 Hz), 5.03 (1H, d,
J ) 17.1 Hz), 5.52 (1H, dd, J ) 3.0, 11.1 Hz), 5.81-5.88 (1H,
m), 5.90 (1H, d, J ) 3.4 Hz), 6.00 (1H, dd, J ) 1.9, 11.0 Hz),
7.33-7.43 (5H, m); 13C NMR δ 27.1 (CH3), 27.4 (CH3), 31.3 (CH2),
39.7 (CH), 43.7 (CH), 43.9 (CH), 46.3 (CH), 67.5 (CH2), 82.3 (C),
82.9 (CH), 90.2 (CH), 104.6 (CH), 113.8 (C), 113.9 (CH2), 127.4
(CH), 127.9 (CH), 128.0 (CH), 128.5 (CH), 138.2 (C), 140.9 (CH),
141.2 (CH), 204.4 (CO); HRMS (ESI) m/z (M + Na)+ calcd for
C24H28O5Na 419.1834, found 419.1836.
Synthesis of the Tricyclic Ketone (23a). Compound 11a (100
mg, 0.25 mmol) in DCM (50 mL) on treatment with catalyst 18
(15 mg, 0.018 mmol) for 1 h first produced the ring opened product
22a as revealed by analysis of the spectral data of an aliquot of the
reaction mixture: [R]26D +90.5 (c 1.14, CHCl3); IR νmax 1709 cm-1
;
1H NMR δ 1.34 (3H, s), 1.57 (3H, s), 1.73-1.93 (4H, m),
2.40-2.54 (1H, m), 2.88-3.00 (1H, m), 3.51-3.66 (1H, m),
4.61-4.65 (2H, m), 4.76 (1H, d, J ) 11.1 Hz), 4.85 (1H, s),
4.93-5.09 (4H, m), 5.29 (1H, d, J ) 17.6 Hz), 5.38 (1H, d, J )
11.1 Hz), 5.55-5.67 (2H, m), 5.77-5.88 (1H, m), 5.92 (1H, d, J
) 3.3 Hz), 7.31-7.39 (5H, m); 13C NMR δ 27.0 (CH3), 27.1 (CH3),
33.6 (CH2), 39.6 (CH2), 43.8 (CH), 47.6 (CH), 51.7 (CH), 67.4
(CH2), 81.5 (CH), 86.2 (C), 87.1 (CH), 104.1 (CH), 113.4 (CH2),
113.4 (C), 115.9 (CH2), 118.9 (CH2), 126.9 (CH), 127.6 (CH), 128.4
(CH), 133.6 (CH), 138.4 (C), 139.2 (CH), 141.8 (CH), 206.1 (CO);
HRMS (ESI) m/z (M + Na)+ calcd for C26H32O5Na 447.2148, found
447.2146. Continuation of the reaction on addition of catalyst 19
(12 mg, 0.014 mmol) in the same pot for 10 h afforded after
1
1717 cm-1; H NMR δ 1.40 (3H, s), 1.46 (1H, m), 1.59 (6H, s),
1.62 (3H, s), 1.75-1.86 (1H, m), 1.96-2.09 (4H, m), 2.97-3.03
(1H, m), 4.67 (2H, s), 4.75 (1H, d, J ) 11.3 Hz), 4.91 (1H, s),
5.31 (1H, d, J ) 17.7 Hz), 5.41 (1H, d, J ) 11.2 Hz), 5.64-5.73
(1H, m), 5.96 (1H, d, J ) 3.4 Hz), 7.27-7.38 (5H, m); 13C NMR
δ 18.9 (CH3), 19.1 (CH3), 24.5 (CH2), 26.7 (CH3), 27.1 (CH3), 31.2
(CH2), 34.1 (CH2), 44.8 (CH), 67.2 (CH2), 81.4 (CH), 85.2 (CH),
86.2 (C), 104.4 (CH), 113.4 (C), 119.3 (CH2), 124.1 (C), 125.5
(C), 126.9 (CH), 127.5 (CH), 128.4 (CH), 133.8 (CH), 138.3 (C),
209.1 (CO); HRMS (ESI) m/z (M + Na)+ calcd for C25H32O5Na
435.2148, found 435.2148.
Lewis Acid Catalyzed Diels-Alder Reaction of Dienophile
4a with Cyclopentadiene. ((3aR,5S,6S,6aR)-6-(Benzyloxy)dihydro-
2,2-dimethyl-6-vinyl-5H-furo[3,2-d][1,3]dioxol-5yl)(bicyclo[2.2.1]hept-
5-en-2yl)methanone (11a). To a magnetically stirred solution of
dienophile 4a (85 mg, 0.26 mmol) in DCM (5 mL) at - 78 °C
was added ZnCl2 (140 mg, 1.06 mmol) then the mixture was stirred
for 15 min followed by addition of freshly distilled cyclopentadiene
(103 mg, 1.56 mmol). After being stirred for 3 h, the reaction
mixture was quenched with brine (0.5 mL) and worked up in the
usual way to afford after column chromatography the adduct 11a
(85 mg, 84%). The spectral data of this compound are identical
with those of the compound obtained above in the noncatalyzed
reaction.
chromatographic purification the tricyclic compound 23a (80 mg,
1
80%): [R]24 +40.4 (c 2.6, CHCl3); IR νmax 1714 cm-1; H NMR
D
δ 1.14-1.25 (1H, m), 1.31 (3H, s), 1.54 (3H, s), 1.78-1.84 (2H,
m), 2.14-2.23 (1H, m), 2.35-2.45 (1H, m), 3.16-3.20 (1H, m),
3.53-3.58 (1H, m), 4.35 (1H, d, J ) 3.0 Hz), 4.47 (1H, d, J )
11.6 Hz), 4.68 (1H, d, J ) 11.7 Hz), 4.77 (1H, s), 4.88 (1H, d, J
) 10.2 Hz), 4.99 (1H, d, J ) 17.1 Hz), 5.35 (1H, dd, J ) 2.1, 12.9
Hz), 5.68-5.79 (3H, m), 7.17-7.29 (5H, m); 13C NMR δ 27.0
(CH3), 27.5 (CH3), 32.7 (CH2), 38.6 (CH), 41.9 (CH), 42.6 (CH2),
52.9 (CH), 67.7 (CH2), 84.3 (C), 84.9 (CH), 85.4 (CH), 104.3 (CH),
114.0 (CH), 114.4 (C), 125.3 (CH), 127.5 (CH), 127.6 (CH), 128.3
(CH), 138.7 (C), 139.1 (CH), 141.2 (CH), 208.7 (CO); HRMS (ESI)
m/z (M + Na)+ calcd for C24H28O5Na 419.1834, found 419.1833.
General Procedure for Metathesis. The general procedure for
metathesis is illustrated by the synthesis of bicyclo-annulated sugar
21a. A magnetically stirred solution of the compound 10a (100
mg, 0.25 mmol) in DCM (50 mL) at -78 °C was saturated by
Acknowledgment. S.G. thanks the Department of Science
and Technology, Government of India for a Ramanna Fellow-
1962 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of Fused Cyclic Systems
ship. C.K.M. thanks CSIR, New Delhi for a Senior Research
Fellowship. M.G.B.D. thanks EPSRC and the University of
Reading for funds for the X-Calibur system.
compound 10d, copies of 1H and 13C NMR spectra of
compounds 4a-e, 5a-e, 6a-e, 7, 8, 9, 10a-d, 11a-d, 15,
16, and 17, 20a,b,d, 21a-d, 22a,c,d, 23a-d, 24, and 25 and
copies of NOESY spectra of compounds 21a and 23a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: General methods and
procedures along with spectral data for compounds 4a-e, 5b-e,
6b-e, 7, 8, 9, 10b-d, 11b-d, 15, 16, and 17, 21b-d, 23b-d,
24, and 25 and X-ray crystal data with ORTEP plot for
JO802077T
J. Org. Chem. Vol. 74, No. 5, 2009 1963