Total synthesis of two possible diastereomers of (+)-sarcophytonolide C and its structural elucidation

Article abstract of DOI:10.1021/ol400157s

Stereoselective and parallel total syntheses of two possible diastereomers of (+)-sarcophytonolide C have been accomplished. Macrolactonization and transannular ring-closing metathesis (RCM) were the key transformations. Detailed comparisons of their

Full text of DOI:10.1021/ol400157s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Total Synthesis of Two Possible
Diastereomers of (þ)-Sarcophytonolide C
and Its Structural Elucidation
Hiroyoshi Takamura,* Kohei Iwamoto, Eiji Nakao, and Isao Kadota*
Department of Chemistry, Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
takamura@cc.okayama-u.ac.jp; kadota-i@cc.okayama-u.ac.jp
Received January 18, 2013
ABSTRACT
Stereoselective and parallel total syntheses of two possible diastereomers of (þ)-sarcophytonolide C have been accomplished. Macro-
lactonization and transannular ring-closing metathesis (RCM) were the key transformations. Detailed comparisons of their 1H and 13C NMR data
and specific rotation with those of the natural product allowed the absolute configuration of (þ)-sarcophytonolide C to be determined.
Cembranolide diterpenes are secondary metabolites iso-
lated from gorgonian octocorals and soft corals.1 Most of
them have been regarded as defensive, competitive, repro-
ductive, and pheromonal substances, which play a func-
tional role in the survival of the corals.1a In addition,
cembranolides often exhibit a wide range of biological
activities such as cytotoxic,2 ichthyotoxic,3 antifungal,4
and antiviral activities.5 Some time ago, Guo’s group
isolated a series of cembranolide diterpenes, sarcophyto-
nolides, from the soft corals of the genus Sarcophyton.6
The structures of the representative molecules, sarcophy-
tonolides C (1), E (2), and H (3), are presented in Figure 1.
They have a 14-membered macrocycle and a butenolide
moiety as common structures. It has been reported that
sarcophytonolide J exhibits potent antifouling activity
against the larval settlement of barnacle Balanus
amphitrite.7 To date, there have been no reports on the
total synthesis of sarcophytonolides.8 The planar structure
of (þ)-sarcophytonolide C (1) was determined by NMR
1
including 1Hꢀ H COSY and HMBC spectra and compar-
ison of its NMR data with those of the known cembrano-
lide, brassicolide.6a The relative configuration at the C1
and C2 positions of 1 was elucidated by NOE difference
experiments. However, the stereochemistry at the C8
position, which is a stereocenter remote from the C1 and
C2 positions, was not clarified. Herein, we report stereo-
selective and parallel total syntheses9 of two possible
diastereomers of (þ)-sarcophytonolide C (1) and the com-
parison of their spectroscopic data with those of the
natural product, which has resulted in the structural
elucidation of 1.
(1) (a) Coll, J. C. Chem. Rev. 1992, 92, 613. (b) Roethle, P.; Trauner,
D. Nat. Prod. Rep. 2008, 25, 298. (c) Li, Y.; Pattenden, G. Nat. Prod.
Rep. 2011, 28, 429.
(2) (a) Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron
Lett. 1988, 29, 4731. (b) Duh, C.-Y.; Wang, S.-K.; Weng, Y.-L.; Chiang,
M. Y.; Dai, C.-F. J. Nat. Prod. 1999, 62, 1518.
(3) Uchio, Y.; Eguchi, S.; Kuramoto, J.; Nakayama, M.; Hase, T.
Tetrahedron Lett. 1985, 26, 4487.
(4) Elsayed, K. A.; Hamann, M. T. J. Nat. Prod. 1996, 59, 687.
(5) Cheng, S.-Y.; Chuang, C.-T.; Wen, Z.-H.; Wang, S.-K.; Chiou, S.-F.;
Hsu, C.-H.; Dai, C.-F.; Duh, C.-Y. Bioorg. Med. Chem. 2010, 18, 3379.
(6) (a) Jia, R.; Guo, Y.-W.; Mollo, E.; Cimino, G. Helv. Chim. Acta
2005, 88, 1028. (b) Jia, R.; Guo, Y.-W.; Mollo, E.; Gavagnin, M.;
Cimino, G. J. Nat. Prod. 2006, 69, 819. (c) Yan, X.-H.; Li, Z.-Y.; Guo,
Y.-W. Helv. Chim. Acta 2007, 90, 1574.
Figure 1. Structures of sarcophytonolides C (1), E (2), and H (3).
r
10.1021/ol400157s
XXXX American Chemical Society

Our retrosynthetic analysis of 1a and 1b, which are
two possible diastereomers of (þ)-sarcophytonolide C, is
outlined in Scheme 1. We envisaged that the cembranolide
framework of 1a and its 8-epimer 1b, which features the
14-membered macrocycle and the butenolide unit, could
be constructed by applying the combination of macro-
lactonization10 and transannular ring-closing metathesis
(RCM)11 to hydroxycarboxylic acids 4a and 4b, respec-
tively.12 The key synthetic intermediates 4a and 4b were
broken down into three fragments, sulfone 5, allylic bro-
mides 6a and 6b, and allylic metal reagent with the ester
group 7. The sulfone 5 could be synthesized from the com-
mercially available cis-2-butene-1,4-diol. The allylic bromides
6a and 6b could be derived from (S)- and (R)-citronellols in
optically pure form, respectively.
Our stereoselective synthesis of sulfone 13 is depicted in
Scheme 2. Monosilylation of cis-2-butene-1,4-diol with TBSCl
and subsequent Sharpless asymmetric epoxidation13 with (þ)-
diethyl tartrate (DET) afforded epoxy alcohol 8. Its enantio-
meric ratio of 17:1 was determined by the 1H NMR compar-
ison of (S)-and(R)-MTPA esters prepared from 8. Treatment
of the epoxy alcohol 8with isopropenylmagnesium bromide in
the presence of CuBr SMe214 provided the desired 1,3-diol 9in
3
84% yield.15 The alkene moiety of 9 was hydrogenated with
(Ph3P)3RhCl to yield alkane 10.16 The primary hydroxy group
of the diol 10 selectively reacted with (PhS)2/n-Bu3P to give
sulfide 11. TBS-protection of the secondary alcohol 11 fol-
lowed by oxidation17 of sulfide 12 produced the sulfone 13.
Scheme 3. Synthesis of 18a and 18b
Scheme 1. Retrosynthetic Analysis of 1a and 1b
Scheme 2. Synthesis of 13
(9) For a parallel synthetic strategy in the natural product synthesis,
see: (a) Fujii, T.; Ohba, M.; Yonezawa, A.; Sakaguchi, J. Chem. Pharm.
Bull. 1987, 35, 3470. (b) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S.
J. Org. Chem. 2002, 67, 5176.
(10) For a review of macrolactonization, see: Parenty, A.; Moreau,
X.; Campagne, J.-M. Chem. Rev. 2006, 106, 911.
€
(11) For reviews of RCM, see: (a) Furstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012. (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490.
(12) Instead of a macrolactonization/transannular RCM sequence,
an RCM/lactonization sequence could be utilized to construct the
cembranolide framework. However, it can be difficult to predict the E/
Z-selectivity of the product in RCM. Therefore, we chose the macro-
lactonization/transannular RCM strategy.
(7) Wang, C.-Y.; Chen, A.-N.; Shao, C.-L.; Li, L.; Xu, Y.; Qian,
P.-Y. Biochem. Syst. Ecol. 2011, 39, 853.
(8) For a synthetic study of sarcophytonolides, see: Fernandes, R. A.;
Ingle, A. B. Tetrahedron Lett. 2011, 52, 458.
B
Org. Lett., Vol. XX, No. XX, XXXX

We next investigated the coupling of the sulfone 13 with
allylic bromides 14a and 14b (Scheme 3). Thus, deprotona-
tion of 13 with NaHMDS and subsequent reaction with the
optically active 14a and 14b, which was prepared from (S)-
and (R)-citronellols,18 gave the desired coupling products 15a
and 15b in 88% and 91% yields, respectively. Reductive
desulfonylation of 15a,b was carried out under Birch condi-
tions,19 wherein the Piv groups were partially removed.20
Protection of the resulting alcohols with PivCl/pyridine
provided the corresponding pivalates. The primary TBS
moieties were selectively deprotected to afford alcohols 16a
and 16b. TEMPO/PhI(OAc)2 (BAIB) oxidation21 of 16a,b
followed by Wittig methylenation provided alkenes 17a and
17b. Treatment of 17a,b with DIBAL-H produced alcohols
18a and 18b in 97% and 98% yields, respectively.
Next, we examined the synthesis of hydroxycarboxylic
acids 23a and 23b which were the macrolactonization pre-
cursors (Scheme 4). TEMPO/BAIB oxidation21 of 18a,b
gave the corresponding aldehydes. Treatment of the result-
ing aldehydes with ethyl (2-bromomethyl)acrylate (19)/
zinc dust in THF/aqueous NH4Cl at 0 °C22 provided the
desired allylated products 20a and 20b as 1:1 diastereo-
meric mixtures in 79% and 93% yields in two steps,
respectively. Protection of the resulting hydroxy moieties
of 20a,b afforded MOM ethers 21a and 21b. The TBS
protective groups of 21a,b were removed with TBAF to
yield alcohols22a and 22b. Alkaline hydrolysis ofthe esters
22a,b with LiOH H2O produced the hydroxycarboxylic
3
acids 23a and 23b, respectively.
Scheme 5. Completion of the Total Synthesis of 1a and 1b
Scheme 4. Synthesis of 23a and 23b
With the key synthetic intermediates 23a and 23b in
hand, we next focused on the construction of the cembra-
nolide skeleton and completion of the total synthesis
(Scheme 5). The hydroxycarboxylic acids 23a,b were trea-
ted with 2-methyl-6-nitrobenzoic anhydride (MNBA)/
DMAP10,23 to afford 15-membered macrolactones 24a
(13) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974. (b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(14) Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131.
(15) For the stereochemical confirmation of 9, see Supporting
Information.
(16) Astles, P. C.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1997, 845.
(17) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.
(20) Pinnick, H. W.; Fernandez, E. J. Org. Chem. 1979, 44, 2810.
(21) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
(22) (a) Mattes, H.; Benezra, C. Tetrahedron Lett. 1985, 26, 5697. (b)
Hanessian, S.; Park, H.; Yang, R.-Y. Synlett 1997, 351.
ꢀ
(18) Soucy, P.; L’Heureux, A.; Toro, A.; Deslongchamps, P. J. Org.
Chem. 2003, 68, 9983.
(19) (a) Dodd, D. S.; Oehlschlager, A. C. J. Org. Chem. 1992, 57,
2794. (b) Blackburn, T. J.; Helliwell, M.; Kilner, M. J.; Lee, A. T. L.;
Thomas, E. J. Tetrahedron Lett. 2009, 50, 3550.
Org. Lett., Vol. XX, No. XX, XXXX
C

and 24b in 85% and 78% yields, respectively. The MOM
groups of 24a,b were deprotected with BF3 OEt2/Me2S24
3
Table 1. Selected Chemical Shift Differences in ppm between
Natural (þ)-Sarcophytonolide C and the Synthetic Products 1a
and 1b in the 1H and 13C NMR (CDCl3)a
to yield alcohols 25a and 25b. The trienes 25a,b were sub-
jected to the transannular RCM11 using the second-
generation HoveydaꢀGrubbs catalyst25 in toluene at 100 °C
to give the desired 14-membered macrocycles with the bute-
nolide moieties 26a and 26b.26 In these reactions, the trienes
25a and 25b were recovered in 38% and 37% yields. Finally,
oxidation of 26a,b with TPAP/NMO27 furnished the target
molecules 1a and 1b in 27% (43% based on recovered
starting material 25a) and 30% (48% based on recovered
starting material 25b) yields over two steps, respectively.28
Having completed the total syntheses of 1a and 1b, we
next submitted these two synthetic products to detailed 2D
1H NMR (ΔδNꢀS
)
13C NMR (ΔδNꢀS
)
position
7
1a
1b
1a
1b
0.00
0.00
ꢀ0.19
þ0.28
ꢀ0.13
ꢀ0.04
þ0.16
þ0.07
ꢀ0.10
ꢀ0.08
0.0
ꢀ0.1
8
9
0.00
0.0
0.0
þ0.2
ꢀ1.1
þ0.01
ꢀ0.01
þ0.01
þ0.01
0.00
10
11
ꢀ0.1
þ0.1
ꢀ1.0
ꢀ1.1
1
1
NMR examination. After analyzing the Hꢀ H COSY,
HMQC, and HMBC NMR spectra, the 1H and 13C NMR
data of 1a were found to be in full agreement with those
reported for the natural product.6a,29 On the other hand,
the 1H and 13C NMR data of 1b were clearly different from
those of the natural product.6a,29 The selected chemical
shift differences between the natural product and the
synthetic products 1a and 1b are described in Table 1.
Significant deviations between the natural product and the
synthetic 1b were observed at the C7, C8, and C9 positions
in the 1H NMR data and at the C9, C10, and C11 positions
in the 13C NMR data. The measured specific rotation of
a NMR spectra of the natural product and the synthetic products
were recorded at 400 MHz (100 MHz). Chemical shifts are reported in
ppm with reference to the internal residual solvent (1H NMR, CHCl3
7.26 ppm; 13C NMR, CDCl3 77.0 ppm). δN and δS are chemical shifts of
the natural product and the synthetic product, respectively.
In conclusion, we have achieved stereoselective and
parallel total syntheses of two possible diastereomers of
(þ)-sarcophytonolide C, wherein the combination of
macrolactonization and transannular ring-closing metath-
esis was utilized for the construction of the cembranolide
skeleton. Detailed comparisons of the synthetic products 1a
and 1b with the natural product revealed the absolute stereo-
chemistry of (þ)-sarcophytonolide C to be that shown in 1a.
Further studies toward the total synthesis of other sarcophy-
tonolides by using the macrolactonization/transannular ring-
closing metathesis sequence are currently underway.
the synthetic 1a, [R]29 þ92.2 (c 0.19, CHCl3), was con-
D
sistent with the value of the natural product, [R]20D þ31.0
(c 0.20, CHCl3).6a,30,31 Therefore, the absolute configura-
tion of (þ)-sarcophytonolide C was elucidated to be 1S,
2S, and 8S as depicted in 1a.
(23) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822.
(24) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S.
J. Org. Chem. 1995, 60, 4419.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(26) For the total synthesis of (ꢀ)-(Z)-deoxypukalide, which is a non-
natural furanocembranolide, by utilizing a transannular RCM, see:
Donohoe, T. J.; Ironmonger, A.; Kershaw, N. M. Angew. Chem., Int.
Ed. 2008, 47, 7314.
(27) For a review of TPAP oxidation, see: Ley, S. V.; Norman, J.;
Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
(28) The epimers at the C1 and C2 positions of 1a and 1b, derived
from the minor enantiomer of 8, could be separated by silica gel column
chromatography at this stage, respectively.
Acknowledgment. We are grateful to Division of Instru-
mental Analysis, Okayama University, for the NMR
measurements. This work was supported by a Grant-in-
Aid for Scientific Research (No. 24710250) from Japan
Society for the Promotion of Science (JSPS).
Supporting Information Available. Stereochemical con-
firmation of 9, detailed comparison of the NMR data
between natural (þ)-sarcophytonolide C and synthetic 1a
and 1b, experimental procedures, spectroscopic data, and
copies of NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(29) See Supporting Information for details.
(30) The synthetic 1b: [R]29D þ97.4 (c 0.21, CHCl3).
(31) The purity of the synthetic product 1a was unambiguously con-
firmed by its NMR data. Because the natural product is not available for us at
present, it is difficult to deeply discuss the absolute value difference of specific
rotations between the synthetic 1a and the natural product.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX