Spirolactone syntheses through a rhodium-catalyzed intramolecular C-H insertion reaction: Model studies towards the synthesis of syringolides

Article abstract of DOI:10.1016/j.tetlet.2009.08.126

Model studies towards the total synthesis of syringolides using a rhodium-catalyzed intramolecular C-H insertion reaction as the key step are described. A highly stereospecific synthesis of spirolactones is achieved employing this methodology.

Full text of DOI:10.1016/j.tetlet.2009.08.126

Tetrahedron Letters 50 (2009) 6450–6453
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Spirolactone syntheses through a rhodium-catalyzed intramolecular C–H
insertion reaction: model studies towards the synthesis of syringolides q
*
Mauricio Navarro Villalobos , John L. Wood
Sterling Chemistry Laboratory, Yale University, New Haven, CT 06520-8107, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Model studies towards the total synthesis of syringolides using a rhodium-catalyzed intramolecular C–H
insertion reaction as the key step are described. A highly stereospecific synthesis of spirolactones is
achieved employing this methodology.
Received 31 July 2009
Revised 26 August 2009
Accepted 27 August 2009
Available online 2 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Syringolides
Spirolactones
C–H insertion
Rhodium(II) stabilized carbene
Stereospecific
The syringolides are a family of nonproteinaceous specific elic-
itors of the hypersensitive response (HR) of plants, an active mech-
anism of defense that involves cell death in the site of infection,
and a complex series of biochemical changes in the plant that re-
strict the pathogen’s proliferation, allowing the plant to resist
pathogen infection.2 In 1993 Sims and co-workers3 reported the
isolation of syringolide 1 (1) and syringolide 2 (2), which are bac-
terial signal molecules (elicitors) produced by the avirulence gene
D (avrD) of Pseudomonas syringae pv. tomato. The syringolides elicit
a HR on soybean cultivars carrying the resistance gene Rpg4.
Through a combination of NMR experiments and X-ray crystallog-
raphy, Sims determined the structures of syringolides as illustrated
in Scheme 1. Syringolides have attracted a great deal of attention
from the synthetic community. Since Wood’s first report4, there
have been ten total syntheses of syringolides 1 and 25 and two for-
mal ones.6 We recently reported the first synthesis of syringolide
3.7
using a C–H insertion as the key step was devised. Accordingly the
retrosynthetic analysis shown in Scheme 1 was conceived. As illus-
trated, the hemiacetals of syringolides (1–3) were envisioned to
arise via intramolecular ring closure from ketones 4a–c. The spiro-
lactone rings in 4a–c would arise from an intramolecular C–H
insertion reaction applied to the
a-diazoesters 5a–c. The requisite
a-diazoesters 5a–c would be synthesized by acylation of a primary
alcohol such as 6 with the corresponding b-ketoacids 7a–c, fol-
lowed by a diazo transfer reaction.
Rather than synthesizing advanced intermediates 5a–c, it was
decided to first explore the C–H insertion key step with a series
of model systems where the lateral chain and the trans diol would
O
n
OH
O
O
O
H
n
n
O
O
O
O
HO
N
2
O
O
O
In 1995, Doyle and Dyatkin8 reported the use of a regioselective
intramolecular carbon–hydrogen insertion reaction to access spi-
rolactones akin to those found in the syringolide core. Thus, with
an interest in improving the syringolide synthesis, a new approach
H
HO
HO
HO
HO
Syringolide 1 (1), n = 3
Syringolide 2 (2), n = 5
Syringolide 3 (3), n = 1
O
4a,
n = 3
4b, n = 5
4c, n = 1
5a, n = 3
5b, n = 5
q
O
O
5c
, n = 1
Portions of this work have appeared as a thesis dissertation.
OH
H
* Corresponding author at present address: Cornell University, Department of
Chemistry & Chemical Biology, Baker Laboratory, Ithaca, NY 14853, USA. Tel.: +1
607 255 3001; fax: +1 607 255 4137.
E-mail addresses: navarro@aya.yale.edu, mn382@cornell.edu, mnavarrovillalo-
bos@gmail.com (M. Navarro Villalobos).
HO
OH
n
+
O
7a, n = 3
7b
, n = 5
7c, n = 1
HO
6
Present address: Chemistry Department, Colorado State University, Fort Collins,
CO 80523, USA.
Scheme 1. Syringolides retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.126

M. Navarro Villalobos, J. L. Wood / Tetrahedron Letters 50 (2009) 6450–6453
6451
Table 3
be masked with suitable precursors. When treated with a rho-
C–H insertions using diazoacetates9 (yield)
dium(II) catalyst such as Rh2(OAc)4, these precursors would be ex-
pected to undergo the desired intramolecular C–H insertion8
producing the corresponding model spirolactones.
Diazo Compound
C-H insertion product
O
O
O
To fully explore how electronics, sterics, and substitution
parameters impact the success of the C–H insertion we decided
to investigate several classes of substituted diazo acetates: aryl
(Table 1), vinyl (Table 2), H (Table 3), and b-carbonyl (Figure 2).
Each one of the resulting C–H insertion products could be ad-
vanced to the target structures. Additionally, the diol-coupling
partner was used as is or masked either as a protected trans diol
or an olefin. To assess reactivity of the various side chains towards
C–H insertion chemistry, the parent tetrahydrofuran was also in-
cluded in our model studies.
O
O
O
N
2
36 (52%)
40 (0%)
O
O
O
O
O
O
N
2
OR
RO
OR
RO
37 R = TBS (82%)
41 R = TBS (69%)
42
38 R = Me (68%)
R = Me (54%)
(+)-43
Table 1
(+)-39
R = Bn (84%)
R = Bn (7%)
C–H insertions using aryl diazoacetates9 (yield)
Diazo Compound
C-H insertion product
Tables 1–3 and Figure 2 depict all the C–H insertion experi-
ments performed.9 In the cases where the reaction conditions
failed to promote the formation of the desired spirolactone, an
intractable mixture of compounds was produced instead. When-
ever two diastereomers could be formed in the C–H insertion reac-
tion, only one was observed by 1H NMR.
O
O
O
O
MeO
O
O
MeO
H
N
2
8 meta; tetrahydrofuranyl (81%)
9 meta; dihydrofuranyl (78%)
15 meta; tetrahydrofuranyl (85%)
16 meta; dihydrofuranyl (73%)
Table 1 shows the C–H insertion results when aryl diazoacetates
10
17
para; dihydrofuranyl (63%)
para; dihydrofuranyl (43%)
are employed. The
a-diazoesters 8–13 required for the desired
intramolecular C–H insertion reactions were synthesized by acyla-
tion of an alcohol10 followed by a diazo transfer reaction.11 For the
synthesis of 14, the parent ester of 11 was desilylated and then in
one pot the corresponding diol underwent transient protection
with 2-methoxypropene, diazo transfer, and finally diol deprotec-
tion. These electron-rich activated diazoacetates gave the best
insertion results when tetrahydro and dihydrofuranyl rings were
used (8–10). However, when either the protected or unprotected
trans-diol substrates were used the reaction worked very poorly
(11–12) or not at all (13–14). Interestingly, single-crystal X-ray
analysis of C–H insertion products established that spirolactones
15–1812 all possessed the same relative stereochemistry (i.e., the
O
O
O
O
MeO
O
O
MeO
N
2
H
RO
OR
OR
RO
11
18 R = TBS (36%)
(-)-19 R = Bn (15%)
R = TBS (67%)
(+)-12 R = Bn (79%)
13 R = Me (32%)
14 R = OH (44%)
20
21
R = Me (0%)
R = OH (0%)
tetrahydrofuranyl oxygen and the proton
a to the lactone carbonyl
Table 2
C–H insertions using vinyl diazoacetates9 (yield)
were always oriented anti about the lactone ring, Fig. 1). This is the
thermodynamically more favorable product, which positions the
sterically hindered side chain on the same side as the tetrahydrof-
uranyl oxygen. By analogy, it is believed that 19 and 29–32 (Tables
1 and 2) also have the same relative stereochemical configuration.
Although this relative configuration is opposite to that needed for
the synthesis of the syringolides (cf. 3 to 18), the potential epimer-
Diazo Compound
C-H insertion product
O
O
O
O
O
O
N
2
izability of the
a-center renders the stereochemical outcome sec-
ondary in importance compared to the formation of the C–C bond.
Table 2 presents C–H insertion results using vinyl diazoacetates.
Vinyldiazocarboxylate 22 was obtained as 8–13 while 23 was pre-
pared from the corresponding diazoacetate8 and cyclohexanone via
the two-step condensation-dehydration procedure developed by
Padwa and co-workers.13 2-Diazo-3-[(t-butyldimethylsilyl)oxy]-
3-butenoates 24–28 were obtained by silylation of the corresponding
diazoacetoacetates. In these experiments we observed the same
trend as for Table 1, with the tetrahydro and dihydrofuranyl rings
(22–25)producingthedesiredC–Hinsertionproductswhilethemore
sterically demanding protected trans-diol moieties (26–28) failed to
form the corresponding spirolactones. As for these electron-rich side
chains, the vinylic diazoacetates did not work as well (29–30) as their
methoxyphenyl counterparts of Table 1, and when a 2-diazo-3-[(t-
butyl-dimethylsilyl)oxy]-3-butenoate was used instead of a simple
alkene the yields of the C–H insertion product dramatically declined
(31–32) or the reaction did not take place at all (33–35).
29
22 vinyl (34%)
vinyl (36%)
30
cyclohexenyl (51%)
23 cyclohexenyl (70%)
O
O
TBSO
O
O
O
O
N
2
TBSO
tetrahydrofuranyl (18%)
24 tetrahydrofuranyl (100%)
25 dihydrofuranyl (98%)
31
32 dihydrofuranyl (13%)
TBSO
O
O
O
O
O
O
OR
N
2
OR
TBSO
OR
RO
26
R = TBS (100%)
33 R = TBS (0%)
34 R = Bn (0%)
35 R = Me (0%)
(+)-27 R = Bn (93%)
28 R = Me (87%)

6452
M. Navarro Villalobos, J. L. Wood / Tetrahedron Letters 50 (2009) 6450–6453
15
16
17
18
Figure 1. ORTEP plot of C–H insertion product.
strates in this electron-withdrawing structure class fail in the C–
H insertion reaction. Diazomalonate 44 was obtained by acylation
of tetrahydrofurfuryl alcohol with methyl malonyl chloride in the
presence of pyridine14 followed by diazotransfer.7,11 Diazoacetoac-
etates 45–50 were obtained by treating the corresponding alcohols
with diketene in the presence of DMAP15 followed by a diazotrans-
fer reaction.7,11,16 Unfortunately neither the diazomalonate nor the
diazoacetoacetates showed the ability to yield the desired
spirolactones.
O
O
O
O
Rh2(L)4
O
O
X
R
O
R"
R'
R
R"
R'
N
2
O
O
O
O
O
O
O
R
O
O
N
N
2
2
44 R = OMe (68%)
45 R = Me (88%)
46 (82%)
Throughout these experiments we discovered that when a tet-
rahydrofuranyl ring moiety is used for the C–H insertion reaction
the electron-rich 3-methoxyphenyl-acetate side chain gives the
best results (15). The electronically similar vinyl diazoacetates
22–23 also produce the desired spirolactones but the yields are sig-
nificantly lower. In contrast, when a side chain with an electron-
withdrawing group was used, that is, diazomalonate 44 and diazo-
acetate 45, the reaction did not take place. Doyle and Dyatkin had
previously shown that the reaction works well with the unsubsti-
tuted diazoacetate.8 A similar trend was observed when using the
dihydrofuranyl ring moiety, with the best results obtained when
using the electron-rich 3- and 4-methoxyphenylacetate side chains
(9 and 10). Poor yields were obtained with vinyldiazoacetate 25
and no product was obtained when using the electron-withdraw-
ing diazoacetate 46. The unsubstituted diazoacetate 36 also failed
to give the desired C–H insertion product as previously discussed.
Interestingly, when using the protected or unprotected trans-
diol ring moieties sterics seemed to play a more important role
than electronics in the C–H insertion reaction, with the most steri-
cally hindered rings giving better yields in combination with the
least sterically hindered side chains. Thus, the best results were ob-
served when an unsubstituted diazoacetate was used with a TBS-
or methyl-protected diol (37 and 38) although the benzyl analog
(+)-39 gave poor yields probably due to side reactions between
the diazo functionality and the benzylic or aromatic positions of
O
O
47 R = TBS (90%)
(+)-48
O
O
R = Bn (89%)
R = Me (78%)
(+)-50 R = OH (91%)
49
N
2
OR
RO
Figure 2. Unsuccessful b-oxo side-chain C–H insertions9 (yield of diazotransfer).
Table 3 depicts C–H insertion results for diazoacetates. These
diazoacetates 36–39 were obtained by deacylation of the corre-
sponding diazoacetoacetates. This less sterically hindered side
chain gave very different results than the vinyl and methoxyphe-
nyldiazoacetates. Thus, the substrate with the dihydrofuranyl ring
(36), unlike Doyle’s tetrahydrofuranyl analog,8 did not give the de-
sired C–H insertion product probably due to competing detrimen-
tal reaction pathways such as dimerization of the substrate,
cyclopropanation of the double bond, or the formation of an oxo-
nium ylide. However this diazoacetate side chain allowed the ex-
pected spirolactones in good yields when the trans-diol group
was TBS (41) or methyl (42) protected. Interestingly, when a ben-
zyl-protecting group was employed the yield plumbeted [(+)-43].
Finally, Figure 2 shows substrates with a b-oxo side chain. Inter-
estingly and regardless of the nature of the ring moiety, all sub-

M. Navarro Villalobos, J. L. Wood / Tetrahedron Letters 50 (2009) 6450–6453
6453
24, 447–463; (h) Lamb, C. J.; Lawton, M. A.; Dron, M.; Dixon, R. A. Cell 1989, 56,
215–224; (i) Gianinazzi, S.. In Plant–Microbe Interactions; Kosuge, T., Nester, E.
W., Eds.; Macmillan: New York, 1984; Vol. 1, Chapter 13,.
the protecting group. The electron-rich 3-methoxyphenylacetate
side chains also gave the best results with the TBS-protected diol
(11) than with the benzyl-protected one [(+)-12] although the
yields were significantly lower than those for the unsubstituted
diazoacetate. In these cases the methyl-protected diol 13 and the
transiently protected diol 14 failed to give the desired spirolac-
tones. Vinyldiazoacetate side chains 26–28 and the electron-with-
drawing acetoacetates 47–50 similarly failed to produce the
expected C–H insertion product.
It is worthy of notice that a highly stereospecific synthesis of
spirolactones was achieved since in all the cases where two diaste-
reomers could be obtained we only produced one and we believe
this methodology could potentially be employed in the assembly
of other synthetically useful compounds.
3. (a) Smith, M. J.; Mazzola, E. P.; Sims, J. J.; Midland, S. L.; Keen, N. T.; Burton, V.;
Stayton, M. M. Tetrahedron Lett. 1993, 34, 223–226; (b) Midland, S. L.; Keen, N.
T.; Sims, J. J.; Midland, M. M.; Stayton, M. M.; Burton, V.; Smith, M. J.; Mazzola,
E. P.; Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940–2945.
4. Wood, J. L.; Jeong, S.; Salcedo, A.; Jenkins, J. J. Org. Chem. 1995, 60, 286–287.
5. (a) Kuwahara, S.; Moriguchi, M.; Miyagawa, K.; Konno, M.; Kodama, O.
Tetrahedron Lett. 1995, 36, 3201–3202; (b) Kuwahara, S.; Moriguchi, M.;
Miyagawa, K.; Konno, M.; Kodama, O. Tetrahedron 1995, 51, 8809–8814; (c)
Ishihara, I.; Sugimoto, T.; Murai, A. Synlett 1996, 335–336; (d) Ishihara, I.;
Sugimoto, T.; Murai, A. Tetrahedron 1997, 53, 16029–16040; (e) Henschke, J. P.;
Rickards, R. W. Tetrahedron Lett. 1996, 37, 3557–3560; (f) Henschke, J.;
Rickards, R. W. Labelled Cpd. Radiopharm. 1998, 41, 211–220; (g) Honda, T.;
Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 9374–9378; (h) Zeng, C.-M.;
Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1997, 62, 4780–4784; (i) Yu, P.;
Wang, Q.-G.; Mak, T. C. W.; Wong, H. N. C. Tetrahedron 1998, 54, 1783–1788; (j)
Wong, H. N. C. Chin. J. Chem. 2005, 23, 1106–1108; (k) Chênevert, R.; Dasser, M.
Can. J. Chem. 2000, 78, 275–279; (l) Chênevert, R.; Dasser, M. J. Org. Chem. 2000,
65, 4529–4531; (m) Varvogli, A.-A. C.; Karagiannis, I. N.; Koumbis, A. E.
Tetrahedron 2009, 65, 1048–1058.
Acknowledgments
6. (a) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K. Heterocycles 1997, 45, 1895–
1898; (b) Di Florio, R.; Rizzacasa, M. A. Aust. J. Chem. 2000, 53, 327–331.
7. Navarro Villalobos, M.; Wood, J. L.; Jeong, S.; Benson, C. L.; Zeman, Z. L.;
McCarty, C.; Weiss, M. M.; Salcedo, A.; Jenkins, J. Tetrahedron 2009, 65, 8091–
8098.
8. Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035–3038.
9. C–H insertion reaction conditions for all diazo compounds: To a suspension of
Rh2(OAc)4 (1.2–0.5% equiv) in CH2Cl2 at reflux was added dropwise (over a 10 h
This work was supported by Yale University and was performed
in the W6 laboratories of Professor John L. Wood under his leader-
ship. The Camille and Henry Dreyfus Foundation (NF-93-0) and the
American Cancer Society (JFRA-523) provided additional support
through their Junior Faculty Award programs. Dr. Navarro would
like to thank Professor Jón T. Njarðarson for useful comments when
preparing this Letter.
period via syringe pump)
a solution of the diazo compound in CH2Cl2.
Rh2(TFA)4 was also tried with 14 and Rh2(cap)4 with 36.
10. (a) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 7, 522–523; (b)
Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 19, 4475–4478.
11. Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth. Commun. 1987, 17,
1709–1716.
12. The atomic coordinates for structures 3 and 15–18 have been deposited with
the Cambridge Crystallographic Data Centre: Navarro Villalobos, Mauricio.
Thesis1 deposition to the Cambridge Structural Database; (a) 3, deposition
number CCDC 150205; (b) 15, CCDC 150207; (c) 16, CCDC 150206; (d) 17,
CCDC 150209; (e) 18, CCDC 150208.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.126.
References and notes
13. (a) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55, 4144–4153; (b)
Pelliciari, R.; Natalini, B.; Sadeghpour, B. M.; Marinozzi, M.; Snyder, J. P.;
Williamson, B. L.; Kuethe, J. T.; Padwa, A. J. Am. Chem. Soc. 1996, 118, 1–12.
14. Box, V. G. S.; Marinovic, N.; Yiannikouros, G. P. Heterocycles 1991, 32, 245–251.
15. Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. Synthesis 1989, 387–388.
16. Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986, 51, 4077–4078.
Caution: These authors mention MsN3 is potentially explosive. For safety
1. Navarro Villalobos, M. Ph.D. Dissertation, Yale University, 2000.
2. (a) Keen, N. T. Adv. Bot. Res. 1999, 30, 291–328; (b) Strange, R. N. Sci. Prog. 1998,
81, 35–68; (c) Heath, M. C. Eur. J. Plant. Pathol. 1998, 104, 117–124; (d)
Staskawicz, B. J.; Ausubel, F. M.; Baker, B. J.; Ellis, J. G.; Jones, J. D. G. Science
1995, 268, 661–667; (e) Keen, N. T. In Mechanisms of Plant Defense Responses;
Fritig, B., Legrand, M., Eds.; Kluwer Academic: Boston, 1993; pp 3–11; (f) Keen,
N. T. Plant Mol. Biol. 1992, 19, 109–122; (g) Keen, N. T. Annu. Rev. Genet. 1990,
reasons most diazo transfers were performed using p-ABSA.11
.