Application of the Rodriguez-Pattenden photo-ring contraction: Total synthesis and configurational reassignment of 11-gorgiacerol and 11-epigorgiacerol

Article abstract of DOI:10.1021/ol301068h

A stereospecific photochemical ring contraction was used as the key step in the first total synthesis of the marine pseudopteranyl diterpene 11-gorgiacerol and its 11-epimer. The synthesis allowed the correction of the configurations that had been misassigned in the literature. In addition, some novel pseudopteranyl derivatives have been made.

Full text of DOI:10.1021/ol301068h

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2834–2837
Application of the RodriguezꢀPattenden
Photo-Ring Contraction: Total Synthesis
and Configurational Reassignment of
11-Gorgiacerol and 11-Epigorgiacerol
Harald Weinstabl, Tanja Gaich, and Johann Mulzer*
€
University of Vienna, Wahringer Strasse 38, 1090 Vienna, Austria
johann.mulzer@univie.ac.at
Received April 23, 2012
ABSTRACT
A stereospecific photochemical ring contraction was used as the key step in the first total synthesis of the marine pseudopteranyl diterpene
11-gorgiacerol and its 11-epimer. The synthesis allowed the correction of the configurations that had been misassigned in the literature.
In addition, some novel pseudopteranyl derivatives have been made.
The furanocembranoids are a vast family of metabolites
that have received wide attention in the synthetic, biosyn-
thetic, and pharmacological communities.1 Among the
manifold structural modifications and rearrangements of
the furanobutenolide-based cembranoids (I), the photo-
induced ring contraction to the pseudopterane skeleton
(II) (Scheme 1) is most remarkable.
This rearrangement has been postulated in the biosyn-
thetic formation of II, but in vitro, it has been observed
only by two groups so far: first by Rodriguez2 and later by
Pattenden,3 who has also studied the stereochemistry of
the reaction in detail. We now report the application of this
RodriguezꢀPattenden ring contraction in the first total
synthesis4 of two metabolites reported as 11-gorgiacerol
(= 11-pseudopteranol) (1)5 and 11-epigorgiacerol (= 11-
epipseudopteranol) (2)56 (Figure 1). These pseudoptera-
noid diterpenes have been isolated from the gorgonian
coral Pseudopterogorgia acerosa and have been character-
ized by NMR and mass spectrometry. In particular, the
configurations at the carbinol center C-11were assigned by
1
1Hꢀ H NMR coupling constants only.
Scheme 1. Furanocembrane and Pseudopterane Skeletons
(1) For two excellent recent reviews, see: (a) Roethle, P. A.; Trauner,
D. Nat. Prod. Rep. 2008, 25, 298–317. (b) Li, Y.; Pattenden, G. Nat.
Prod. Rep. 2011, 28, 1269–1310.
(2) Rodriguez, A. D.; Shi, J.-G.; Huang, S. D. J. Org. Chem. 1998, 63,
4425–4432.
(3) (a) Yang, Z.; Li, Y.; Pattenden, G. Tetrahedron 2010, 66, 6546–
6549. (b) Li, Y.; Pattenden, G. Tetrahedron Lett. 2011, 52, 3315–3319.
(4) For a profound recent review of photoreactions in total synthesis,
see: Bach, T.; Hehn, J. P. Angew. Chem. 2011, 123, 1032–1077. Angew.
Chem., Int. Ed. Engl. 2011, 50, 1000–1045.
(5) Tinto, W. F.; Laydoo, R. S.; Miller, S. L.; Reynolds, W. F.;
McLean, S. J. Nat. Prod. 1995, 58, 1975–1977.
(6) Kate, A. S.; Richard, K.; Ramanathan, B.; Kerr, R. G. Can. J.
Chem. 2010, 88, 318–322.
r
10.1021/ol301068h
Published on Web 05/16/2012
2012 American Chemical Society

Our synthesis of 1 and 2 has now demonstrated that
these assignments were wrong and have to be permuted so
that the former 11-gorgiacerol is now 11-epigorgiacerol
and vice versa. Thus, Figure 1 shows the former and the
corrected configurations.
Scheme 2. Total Syntheses of 1 and 2
Figure 1. Original and corrected structures of 11-gorgiacerol
and its 11-epimer.
The synthesis (Scheme 2) started with the known7 ester
acetal 3 (readily available in four steps from (R)-(ꢀ)-
carvone). Reduction to the aldehyde, aldol addition of
methyl acetate, and oxidation of the hydroxyl ester af-
forded keto-ester 4. Deprotonation and alkylation with
iodide 5 furnished keto acetylide 6, which was cyclized8 to
the furan under basic conditions. Acid-catalyzed hydro-
lysis of the acetal led to aldehyde 7 which was subjected to
an aldol addition with selenolactone 8.9 Oxidative elimina-
tion of the selenium gave butenolides 9a/b,10 readily
separated by column chromatography. As both epimers
were required for the envisaged structural assignment, no
efforts were spent to improve the stereoselectivity of the
aldol addition.
The synthesis was completed by a photoch emical ring
contraction of 10a and 10b which furnished the desired
pseudopteranes 1 and 2 in acceptable yields. Furan 2
was crystalline, which allowed the unambiguous assign-
ment of its structure by single-crystal X-ray diffraction
(Figure 2).
Ring-closing metathesis (RCM)11 with Grubbs’ second-
generation catalyst gave (Z)-olefins 10a and 10b stereo-
selectively (Scheme 2).
ꢀ
(7) Gonzalez, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis,
E. A. Tetrahedron Lett. 2004, 45, 5039–5041.
(8) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63,
7132–7133.
(9) Gaich, T.; Weinstabl, H.; Mulzer, J. Synlett 2009, 1357–1366.
(10) Cf. Cases, M.; Gonzalez-Lopez de Turiso, F.; Hadjisoteriou,
M. S.; Pattenden, G. Org. Biomol. Chem. 2005, 3, 2786–2804 and
references cited therein..
1H and 13C NMR data were in full agreement with the
published data (see the Supporting Information).
The optical rotations of our samples differ from the
published values but have the same sign (1: [R]20D = þ83.0
(c = 0.33; CHCl3) vs þ22 (c = 0.1, CHCl3);5 2: [R]20
=
D
(11) Some reviews: (a) Schmalz, H.-G. Angew. Chem. 1995, 107,
1981–1984. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833–1836. (b)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450. (c) Arm-
þ130.0 (c = 0.25; CHCl3) vs þ173.2 (c = 0.12, CHCl3).6
An analogous sequence (Scheme 3) was applied to
prepare 11-epigorgiacerol acetate13from 9a/b. Crystalline
acetate 12b was subjected to a single crystal diffraction
(Figure 3). To show that no epimerization occurred at the
C-11 center during the photochemical ring contration,
compound 2 was subjected to an acetylation reaction.
The spectral data of the resulting product were in complete
agreement with those of compound 13.
€
strong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371–388. (d) Furstner,
A. Angew. Chem. 2000, 112, 3140–3172. Angew. Chem., Int. Ed. 2000, 39,
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(f) Trinka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (g)
Gaich, T.; Mulzer, J. Curr Top. Med. Chem. 2005, 5, 1473–1494. (h)
Bohrsch, V.; Blechert, S. Ch. I. U. Z. 2005, 39 (6), 379–380. (i) Martin,
W. H. C.; Blechert, S. Curr. Top. Med. Chem. 2005, 5, 1521–1540. (j)
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Curr. Top. Org. Chem. 2008, 12 (18), 1631–1647. (m) Cossy, J.;
Arseniyadis, S.; Meyer, C.; Grubbs, R. H. Metathesis in Natural Product
Synthesis: Strategies, Substrates and Catalysts; Wiley-VCH: Weinheim,
2010. (n) Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock,
R. R.; Hoveyda, A. H. Nature 2011, 479, 88–89.
On studying the photoreaction of compound 10b in
more detail, we found, in confirmation of Pattenden’s
earlier results,3 that the labile (E)-isomer 14b (Scheme 4)
was produced first and was isolated after 20% conversion.
Org. Lett., Vol. 14, No. 11, 2012
2835

Scheme 3. Synthesis of 11-Epigorgiacerol Acetate 13
Scheme 4. Mechanistic Considerations
In the 1H NMR spectrum of 14b, considerable line broad-
ening was observed at room temperature because of re-
stricted conformation mobility of the highly strained macro-
cyclic ring. On heating to 55 °C, the lines sharpened to give
a resolved spectrum (see the Supporting Information).
On prolonged irradiation, and without reisomerization to
10b, the (E)-olefin 14b underwent ring contraction to 2 with
stereoselective generation of the new chiral center at C-7.
Obviously, no direct isomerization of 10b to 2 is involved. As
pointed out by Pattenden,1b,3 the conversion of 14b into 2
may occur directly via a concerted [1,3]-sigmatropic shift or
via a bis-allylic diradical such as 15b in which the original
configuration at C-10 (numbering as in Scheme 4) is lost. We
do not know the conformation of 14b. However the crystal
structures of 2 and 12b (Figures 2 and 3) show that the
migrating σ-bond stands virtually perpendicular on the
allylic plane. Hence, the conformational situation in such
systems is well suited for a suprafacial 1,3-shift, whether
concerted or stepwise.12
Figure 2. Crystal Structure of 2.
Aiming for novel pseudopterane derivatives (Scheme 5),
acetate 13 was treated with K2CO3 to generate methyl
ether 17 with complete retention of configuration.
As an SN1 mechanism is highly unlikely under the
conditions, this surprising result is interpreted in terms
of an addition/elimination process via 16 (NudOMe),
in which C-11 is attacked by the strongest nucleophile
in the system (=OMe) from the less hindered ring face.
By contrast, the reaction of 13 with methanol under
acidic conditions furnished adduct 18. Remarkably,
only one of the isopropenyl groups was attacked,
and the 11-OH was formed by acidic methanolysis of
Figure 3. Crystal structure of 12b.
the acetate. On attempting the dehydration of alcohol 1
with Burgess’ reagent,13 urethane 21 was obtained
ꢀ
ꢀ
(13) (a) Crabbe, P.; Leon, C. J. Org. Chem. 1970, 35, 2594–2596. (b)
Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–4745. (c)
Review: Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461–
476.
(14) (a) Chan, W. R.; Tinto, W. F.; Laydoo, R. S.; Marchand, P. S.;
Reynolds, W. F.; McLean, S. J. Org. Chem. 1991, 56, 1773–1776. (b)
Tinto, W. F.; John, L.; Reynolds, W. F.; McLean, S. Tetrahedron 1990,
31, 8679–8686.
(12) For similar considerations, see: Kimbrough, T. J.; Roethle,
P. A.; Mayer, P.; Trauner, D. Angew. Chem. 2010, 122, 2675–2678.
Angew. Chem., Int. Ed. 2010, 49, 2619–2621.
2836
Org. Lett., Vol. 14, No. 11, 2012

cheletropic elimination of SO3. The stereochemistry
of the rearrangement may be rationalized in terms
of a six-membered transition state 20, in which the
nitrogen attacks C-9 from the less hindered side.
This assumption is strengthened by the fact that 2
did not undergo rearrangement under the same condi-
tions.
Scheme 5. Synthesis of Pseudopterane Derivatives
In conclusion, we have achieved (1) a concise synthesis
of the pseudopteranyl alcohols 1 and 2 from (R)-(ꢀ)-
carvone in 12 steps (plus two steps for the preparation of
selenolactone 8 from (S)-tosyl glycidol) in 11% and 8%
overall yield; (2) a reassignment of the configuration at
C-11 and a confirmation of the absolute configuration of 1
and 2; (3) a confirmation of the mechanism of the Rodri-
guez-Pattenden ring contraction; and (4) some substrate
directed diastereoselective substitutions on the generic core
which led to novel pseudopteranyl derivatives.
As for the biological properties of 1 and 2, it has been
shown that 2 has cytotoxic activity in the micromolar
range, whereas 1 is inactive.6 Thus, the behavior of our
new pseudopterane derivatives is of interest and will be
investigated in ongoing studies.
€
Acknowledgment. We thank H. Kahlig, L. Brecker, and
S. Felsinger for NMR assistance, A. Roller and V. Arion
for X-ray analysis, and Martina Drescher (all University of
Vienna) for experimental work.
Supporting Information Available. Experimental pro-
cedures and full characterization of all new compounds
including copies of 1H and 13C NMR spectra and crystal
structure analysis of 2 and 12b (CIF). This material is
available free of charge via the Internet at http://pubs.acs.
org.
stereoselectively, which is a close analogue of deoxyto-
bagolide (22).14,15 We postulate that 21 is formed from
primary adduct 19 via a [1,3]-sigmatropic shift with
(15) The relative configuration of 21 has been safely assigned by
1
appropriate 1Hꢀ HꢀNOE effects (see the Supporting Information).
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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