A photocycloaddition/fragmentation approach toward the 3,12- dioxatricyclo[8.2.1.06,13]tridecane skeleton of terpenoid natural products

Article abstract of DOI:10.1021/ol2004462

Starting from tetronate 1 (R = CH₂OH), a short photochemical access to the 3,12-dioxatricyclo[8.2.1.0^6,13]tridecane-skeleton 2 of briarellin and asbestinin diterpenes has been explored. In the course of these studies, a number of sur

Full text of DOI:10.1021/ol2004462

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1892–1895
A Photocycloaddition/Fragmentation
Approach toward the 3,12-
Dioxatricyclo[8.2.1.06,13]tridecane
Skeleton of Terpenoid Natural Products
†
Jorg P. Hehn, Eberhardt Herdtweck, and Thorsten Bach*
‡
,†
€
Lehrstuhl fu€r Organische Chemie I, Lehrstuhl fu€r Anorganische Chemie,
€
Technische Universitat Munchen, Lichtenbergstr. 4, 85747 Garching, Germany
€
thorsten.bach@ch.tum.de
Received February 18, 2011
ABSTRACT
Starting from tetronate 1 (R = CH2OH), a short photochemical access to the 3,12-dioxatricyclo[8.2.1.06,13]tridecane-skeleton 2 of briarellin and
asbestinin diterpenes has been explored. In the course of these studies, a number of surprising observations were made. For example, a two-step
reaction pathway to the bicyclic ketolactone 3 was discovered, which is based on tetronate 1 (R = COOMe).
One of the big advantages of synthetic photochemical
methods is their potential to generate strained ring systems
in good yields and with high stereoselectivity.1 The energy
of the activation by light is, at least partially, conserved in
the ring strain of the product molecules. Many applica-
tions of photochemical procedures in natural product
synthesis2 make elegant use of this feature, either by
forming directly complex natural products with a strained
scaffold or by accessing natural products through selective
cyclobutane cleavage reactions of a strained skeleton.
These reactions are particularly useful for the formation
of seven- to twelve-membered rings. The prototypical
example for a [2 þ 2]-photocycloaddition/fragmentation
sequence is the widely used de Mayo reaction,3 in which a
[2 þ 2]-photocycloaddition is combined with a retro-aldol
reaction. Free radical fragmentations represent a second
class of important cleavage reactions, which enjoy great
popularity in synthesis.4
(4) Examples: (a) Lange, G. L.; Gottardo, C. Tetrahedron Lett. 1990,
31, 5985–5988. (b) Crimmins, M. T.; Dudek, C. M.; Cheung, A. W.-H.
Tetrahedron Lett. 1992, 33, 181–184. (c) Lange, G. L.; Gottardo, C.
Tetrahedron Lett. 1994, 35, 8513–8516. (d) Lange, G. L.; Gottardo, C. J.
Org. Chem. 1995, 60, 2183–2187. (e) Crimmins, M. T.; Huang, S.; Guise-
Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519–6522. (f) Lange, G. L.;
Merica, A.; Chimanikire, M. Tetrahedron Lett. 1997, 38, 6371–6374. (g)
Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J. Am. Chem. Soc. 1998,
120, 1747–1756. (h) Lange, G. L.; Gottardo, C.; Merica, A. J. Org.
Chem. 1999, 64, 6738–6744. (i) Shipe, W. D.; Sorensen, E. J. J. Am.
Chem. Soc. 2006, 128, 7025–7035.
(5) Ellis, J. M.; Crimmins, M. T. Chem. Rev. 2008, 108, 5278–5298.
€
(6) Reviews: (a) Hehn, J. P.; Muller, C.; Bach, T. In Handbook of
Synthetic Photochemistry; Albini, A., Fagnoni, M., Eds.; Wiley-VCH:
Weinheim, 2010; pp 171-215. (b) Fleming, S. A. In Molecular and
Supramolecular Photochemistry, Vol. 12; Griesbeck, A. G., Mattay, J.,
Eds.; M. Dekker: New York, 2005; pp 141-160. (c) Margaretha, P. In
Molecular and Supramolecular Photochemistry, Vol. 12; Griesbeck,
A. G., Mattay, J., Eds.; M. Dekker: New York, 2005; pp 211-237. (d)
Bach, T. Synthesis 1998, 683–703. (e) Pete, J.-P. Adv. Photochem. 1996,
21, 135–216. (f) Mattay, J.; Conrads, R.; Hoffmann, R. In Methoden der
Organischen Chemie (Houben-Weyl), 4th ed., 1952-, Vol. E 21c; Thieme
Verlag: Stuttgart, 1995; pp 3085-3132. (g) Crimmins, M. T.; Reinhold,
T. L. Org. React. 1993, 44, 297–588. (h) Becker, D.; Haddad, N. Org.
Photochem. 1989, 10, 1–162. (i) Crimmins, M. T. Chem. Rev. 1988, 88,
1453–1473. (j) Baldwin, S. V. Org. Photochem. 1981, 5, 123–225.
(k) Bauslaugh, P. G. Synthesis 1970, 287–300.
† Lehrstuhl f€ur Organische Chemie I.
‡ Lehrstuhl f€ur Anorganische Chemie.
(1) (a) Handbook of Synthetic Photochemistry; Albini, A., Fagnoni,
M., Eds.; Wiley-VCH: Weinheim, 2010. (b) Klan, P.; Wirz, J. Photochem-
ꢀ
istry of Organic Compounds: From Concepts to Practice; John Wiley &
Sons: Hoboken, NJ, 2009. (c) Hoffmann, N. Chem. Rev. 2008, 108, 1052–
1103.
(2) Reviews: (a) Iriondo-Alberdi, J.; Greaney, M. F. Eur. J. Org.
Chem. 2007, 4801–4815. (b) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed.
2011, 50, 1000–1045.
(3) Reviews: (a) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev.
1995, 95, 2003–2020. (b) Oppolzer, W. Acc. Chem. Res. 1982, 15, 135–
141. (c) de Mayo, P. Acc. Chem. Res. 1971, 4, 41–47.
r
10.1021/ol2004462
Published on Web 03/07/2011
2011 American Chemical Society

In the context of a project that is directed toward the
synthesis of diterpenoid natural products of the briarellin
and asbestininfamily,5 wewonderedifthecentral coreA of
these compoundsmay be formed via intermediateB, which
in turn could be obtained by an intramolecular [2 þ 2]-
photocycloaddition (Scheme 1).6 This letter reveals pre-
liminary results of our studies, in the course of which two
unexpectedionicringexpansion reactionsofcyclobutanes7
were discovered.
Tetronic acid 311 and the parent compound 212 are
literature known and can be prepared from R-hydroxy-
iso-butyric acid. The coupling of the tetronic acids with
alcohol 1 was accomplished by a Mitsunobu reaction.13
Starting from tetronic acid 2, product 4 was obtained in
93% yield, and starting from tetronic acid 3, substrate 5
was formed (90% yield), which features a methoxycarbo-
nyl group in the R-position (Scheme 2). In the intramole-
cular [2 þ 2]-photocycloaddition of the latter compound,
the crossed product 6 was generated exclusively. This
violation of the ‘rule of five’14,15 (preference of five-
membered ring formation during the [2 þ 2]-photo-
cycloaddition) is remarkable, in particular because the
formal reduction product of the ester 5, the R-tetronate
7, which was formed by hydroxymethylation16 of tetronate
4, gave exclusively the straight photocycloaddition pro-
duct 8 (Scheme 2).
Scheme 1. Retrosynthetic Consideration for the Synthesis of
Dioxatricyclo[8.2.1.06,13]tridecane Scaffold A via Cyclobutane
B
Scheme 2. [2 þ 2]-Photocycloaddition of Tetronate 5 To Afford
Crossed Product 6 and of Tetronate 7 To Afford Straight
Product 8
Tetronates appeared to be particularly useful synthetic
equivalents for the precursor C depicted in Scheme 1. They
have been described as versatile, robust substrates for [2 þ 2]-
photocycloaddition reactions,8 and they have previously
been applied in natural product synthesis.9 As the skeleton
A of the briarellins and asbestinins exhibits a methyl group
at position C5, it appeared sensible to introduce this C1-
unit as part of the tetronate. Thus, we focused our studies on
[2 þ 2]-photocycloadditions of R-substituted tetronates.
Apart from that, a disubstituted γ-position was to be
included in the model substrate in order to mimic the
quarternary carbon atom at the respective position of the
natural products. The synthesis of the [2 þ 2]-photocycload-
dition substrates (cf. Supporting Information) commenced
with the known primary alcohol 1, which is accessible from
cyclohexene in one step (Figure 1).10
Studiestoshedlight onthe unexpected regioselectivityin
the reaction 5 f 6 are in progress. The trivial explanation
that the high stability of the radical at the former
R-position of the tetronate (stabilized by two carbonyl
groups) is responsible for an initial formation of a six-
membered ring cannot hold true because the simple but-3-
(11) Matsuo, K.; Tanaka, T. Chem. Pharm. Bull. 1984, 32, 3724–
3729.
(12) Schobert, R.; Stehle, R.; Walter, H. Tetrahedron 2008, 64, 9401–
9407.
(13) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1967, 40, 935–939. (b) Mitsunobu, O. Synthesis 1981, 1–28. (c)
Bajwa, J. S.; Anderson, R. C. Tetrahedron Lett. 1990, 31, 6973–6976. (d)
Castro, B. R. Org. React. 1992, 42, 335–656.
Figure 1. Structures of starting materials 1-4.
(14) (a) Srinivasan, R.; Carlough, K. H. J. Am. Chem. Soc. 1967, 89,
4932–4936. (b) Liu, R. S. H.; Hammond, G. S. J. Am. Chem. Soc. 1967,
89, 4936–4944.
(7) Reviews: (a) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003,
103, 1485–1583. (b) Wong, H. N. C. In Methoden der Organischen
Chemie (Houben-Weyl), 4th ed., 1952-, Vol. E 17e; Thieme Verlag:
Stuttgart, 1997; pp 435-610. (c) Wong, H. N. C.; Lau, K.-L.; Tam,
K.-F. Top. Curr. Chem. 1986, 133, 83–157.
(15) For exceptions, see: (a) LaLonde, R. T.; Aksentijevich, R. I.
Tetrahedron Lett. 1965, 6, 23–27. (b) Begley, M. J.; Mellor, M.;
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Pattenden, G. Chem. Commun. 1979, 235–236. (c) Alder, A.; Buhler,
N.; Bellus, D. Helv. Chim. Acta 1982, 65, 2405–2412. (d) Ikeda, M.;
Takahashi, M.; Uchino, T.; Ohno, K.; Tamura, Y.; Kido, M. J. Org.
Chem. 1983, 48, 4241–4247. (e) Matlin, A. R.; George, C. F.; Wolff, S.;
Agosta, W. C. J. Am. Chem. Soc. 1986, 108, 3385–3394. (f) Crimmins,
M. T.; Hauser, E. B. Org. Lett. 2000, 2, 281–284. (g) Ng, S. M.; Bader,
S. J.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 7315–7319.
(16) Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007,
9, 1165–1167.
(8) (a) Kemmler, M.; Bach, T. Angew. Chem., Int. Ed. 2003, 42, 4824–
4826. (b) Kemmler, M.; Bach, T. Eur. J. Org. Chem. 2004, 4582–4595. (c)
ꢀ
Hehn, J. P.; Gamba-Sanchez, D.; Kemmler, M.; Fleck, M.; Basler, B.;
Bach, T. Synthesis 2010, 2308–2312.
(9) (a) Fleck, M.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 6189–
6191. (b) Fleck, M.; Bach, T. Chem.;Eur. J. 2010, 16, 6015–6032.
(10) Clausen, R. P.; Bols, M. J. Org. Chem. 2000, 65, 2797–2801.
Org. Lett., Vol. 13, No. 7, 2011
1893

enyl-substituted analogue of 5 afforded predominantly
(regioisomeric ratio r.r. = 90/10) the straight product.
The assignment of the regiosomers is based on extensive
one- and two-dimensional NMR experiments (cf. Sup-
porting Information). Furthermore, the structure of the
crossed photoproduct 6 was unambiguously proven by a
crystal structure analysis (Figure 2, see Supporting Infor-
mation, CCDC 813562).
Scheme 3. Ionic Ring Expansion of [2 þ 2]-Photocycloaddition
Product 6 via Hemiacetal 9 To Afford Ketolactone 10
The high propensity toward ring cleavage reactions of
tetronate photocycloaddition products was confirmed in
other reactions, which are not mentioned here in detail but
which encouraged us to approach the planned radical
fragmentation of product 8. Accordingly, the primary
alcohol 8 was converted into iodide 11, which in turn
was treated with an initiator and a reducing agent
[Bu3SnH or (Me3Si)3SiH19]. Surprisingly, these reactions
led preferably to product 14 (Scheme 4).
Figure 2. Proof of structure and relative configuration of the
crossed product 6 by crystal structure analysis.
Scheme 4. Transformation of the [2 þ 2]-Photocycloaddition
Product 8 into a Precursor of a Radical Fragmentation and
Formation of Tetracycle 14 by a Radical Domino Reaction
Both products 6 and 8 were formed as single diastereo-
isomers; i.e. all four newly formed stereogenic centers were
generated with perfect control of the facial and simple
diastereoselectivity. Diethylether and tert-butanol were
found to be the preferred solvents for the [2 þ 2]-
photocycloaddition of 5 and 7. It is noteworthy that the
reaction of the methoxycarbonyl-substituted tetronate 5
was considerably faster than the reaction of 7. While the
photocycloaddition of the former substrate was complete
after 30 min, an irradiation time of 8 h was required for full
conversion of the latter tetronate. The rate increase is
attributed to the greater absorption of tetronate 5 at the
irradiation wavelength λ = 254 nm.
Another proof for the structure of the crossed product 6
is based on an enormously facile ionic ring expansion,
which took place upon treatment with KOH in aqueous
MeOH (Scheme 3). The seven-membered ketolactone 10
was formed in very good yield via the tricyclic hemiacetal 9
as an intermediate. Apparently, the ring strain facilitates a
nucleophilic substitution of a malonate unitby a hydroxide
ion at position C2 of the tetracyclic substrate 6 under these
conditions.17 The lability of bond C2-C6 of 6 is already
apparent from its unusually long bond length of
Unexpectedly, the anticipated fragmentation toward a
3,12-dioxatricyclo[8.2.1.06,13]tridecane skeleton is clearly
disfavored compared to the fragmentation that affords a
spirocyclic dioxatridecane framework.20 Presumably, the
radical 12 was formed, followed by cyclobutane cleavage
to generate the secondary radical 13. The consecutive
5-endo-cyclization was fast, so that the direct reduction
product of radical 13 was not observed. The conditions
shown in Scheme 4 employing (Me3Si)3SiH as the reducing
agent afforded the best yield of product 14. Attempts to
induce the desired ring expansion by applying reductive
conditions (SmI2)21 to the aldehyde that is derived from
˚
1.575(2) A as determined by X-ray crystallography
(Figure 2).18
(17) (a) Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade,
A. S.; Thomas, J. B.; Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc.
1999, 121, 10249–10250. (b) Crimmins, M. T.; Pace, J. M.; Nantermet,
P. G.; Kim-Meade, A. S.; Thomas, J. B.; Watterson, S. H.; Wagman,
A. S. J. Am. Chem. Soc. 2000, 122, 8453–8463.
(19) (a) Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem.
1988, 53, 3641–3642. (b) Giese, B.; Kopping, B. Tetrahedron Lett. 1989,
30, 681–684. (c) Chatgilialoglu, C. Chem.;Eur. J. 2008, 14, 2310–2320.
(20) For a fragmentation of a cyclobutylcarbinyl radical to generate
an oxysubstituted tertiary radical, see: Hehn, J. P.; Bach, T. Synlett 2009,
1281–1284.
(21) Reviews: (a) Molander, G. A. In Radicals in Organic Synthesis,
Vol. 1; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; pp
153-182. (b) Molander, G. A. Org. React. 1994, 46, 211–367.
(18) The C-C bond distances in the parent cyclobutane have been
˚
determined as 1.552(1)-1.5555(2) A: (a) Vogelsanger, B.; Caminati, W.;
Bauder, A. Chem. Phys. Lett. 1987, 141, 245–250. (b) Egawa, T.;
Fukuyama, T.; Yamamoto, S.; Takabayashi, F.; Kambara, H.; Ueda,
T.; Kuchitsu, K. J. J. Chem. Phys. 1987, 86, 6018–6026.
1894
Org. Lett., Vol. 13, No. 7, 2011

alcohol 8 deliveredproducts, which are formedbythe same
reaction pathway. In this case, a 2,12-dioxatetracyclo-
be converted into iodide 19, i.e. the C3-deoxygenated
analogue of compound 11. Gratifyingly, although some-
what to our surprise, this reaction afforded the depicted
product 20 (Scheme 6). We assume that the iodide 19 is
indeed formed via alcohol 18. However, due to the pre-
sence of an electron-donating substituent at the cyclobu-
tane carbon atom C6, the intermediately formed iodide
undergoes a 1,2-elimination resulting in a Grob frag-
mentation.24,25 After deprotonation of the intermediate
onium ion, product 20 is obtained.
[6.5.1.01,10 4,14
]tetradecane was formed by a similar dom-
0
ino process.22
Since the extended carbon-carbon bond length in cyclo-
butane 6 (Figure 2) had given an indication for the regio-
selectivity of its ring fission (Scheme 3), we were curious
whether similar structural information would give a hint as
to the regioselectivity in the fragmentation of cyclobutyl-
carbinyl radical 12. Iodide11 was unstable, and we therefore
prepared cyclobutane 16 (Scheme 5) as a model to elucidate
the structural properties of radical 12. Cyclobutane 16 was
obtained by the [2 þ 2]-photocycloaddition of tetronate 15,
which in turn was prepared from trimethyltetronic acid23
and alcohol 1 by a Mitsunobu reaction.13 A crystal structure
analysis of 16 (cf. Supporting Information, CCDC 813563)
Scheme 6. Fragmentation of Triol 17 Induced by Reaction with
PPh3 and I2 and Putative Mechanism of the Fragmentation
˚
uncovered a C1-C2 bond length of 1.579(2) A, which is
considerably longer than the remaining three cyclobutane
C-C bonds.18 Quite clearly, the preferred fragmentation of
the bond between C1 and C2 in radical 12 is indeed
facilitated by the intrinsic molecular strain.
Scheme 5. [2 þ 2]-Photocycloaddition of Tetronate 15
The reduction of 3,12-dioxatricyclo[8.2.1.06,13]tridecane
20 to the saturated scaffold was readily achieved. For
example, Et3SiH in the presence of TFA resulted in being
a suitable reductant in preliminary studies. Under these
conditions, product 21 was obtained in a not yet optimized
yield of 66%. However, rather than optimizing conditions
on model systems, current work in our group is directed
toward the application of the fragmentation to advanced
intermediates en route to briarellin diterpenes. We feel that
the other cyclobutane ring cleavage and domino reactions
presented in this letter represent useful extensions to the
organic toolkit, as they open expedient synthetic routes
toward complex structural frameworks. Commencing with
simple starting materials, the products are accessible in less
than five steps in good yields.
The bond cleavage to the desired scaffold A (Scheme 1)
was eventually achieved while trying to form the respective
iodomethyl-substituted tetrahydrofuran after reduction of
the γ-lactone. Subjecting lactone 8 to a reduction with
NaBH4 resulted in the formation of triol 17, which was to
(22) Reviews: (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006; pp
219-279. (b) Dhimane, A. L.; Fensterbank, M.; Malacria, M. In
Radicals in Organic Synthesis, Vol. 1; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; pp 350-382.
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Chem. 1950, 15, 572–582. (b) Anderson, J. R.; Edwards, R. L.; Whalley,
A. J. S. J. Chem. Soc., Perkin Trans. 1 1982, 215–221. (c) Clough, J. M.;
Pattenden, G.; Wight, P. G. Tetrahedron Lett. 1989, 30, 7469–7472.
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3766. (b) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983; pp 257-266. (c) Grob, C. A. Angew.
Chem., Int. Ed. Engl. 1969, 8, 535–546. (d) Grob, C. A.; Schiess, P. W.
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Acknowledgment. This project was supported by the
Deutsche Forschungsgemeinschaft (Ba 1372/11-2). J.P.H.
gratefully acknowledges the support from the Fonds der
ꢀ
Chemischen Industrie through a Kekule scholarship.
(25) Further examples of cyclobutane fragmentations via onium
ions: (a) Kirmse, W.; Mrotzek, U. Chem. Ber. 1988, 121, 1013–1016.
(b) Crimmins, M. T.; Thomas, J. B. Tetrahedron Lett. 1989, 30, 5997–
6000. (c) Gruseck, U.; Heuschmann, M. Chem. Ber 1990, 123, 1905–
1909. (c) Mal, J.; Nath, A.; Venkateswaran, R. V. J. Org. Chem. 1996, 61,
9164–9167. (d) Graziano, M. L.; Iesce, M. R.; Cermola, F.; Ialongo, G.
J. Chem. Soc., Perkin Trans. I 1997, 2155–2160.
Supporting Information Available. Representative ex-
perimental procedures and spectral data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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