Enantioselective synthesis of rumphellaone A via epoxy nitrile cyclization

Article abstract of DOI:10.1016/j.tetlet.2011.11.145

The first enantioselective synthesis of rumphellaone A, a cytotoxic 4,5-seco-caryophyllane derivative incorporating a γ-lactone ring as its structural feature, has been achieved by using base-induced intramolecular cyclization of an epoxy nitrile intermed

Full text of DOI:10.1016/j.tetlet.2011.11.145

Tetrahedron Letters 53 (2012) 705–706
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of rumphellaone A via epoxy nitrile cyclization
⇑
Takafumi Hirokawa, Tomohiro Nagasawa, Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first enantioselective synthesis of rumphellaone A, a cytotoxic 4,5-seco-caryophyllane derivative
Received 9 November 2011
Revised 29 November 2011
Accepted 30 November 2011
Available online 6 December 2011
incorporating a c-lactone ring as its structural feature, has been achieved by using base-induced intramo-
lecular cyclization of an epoxy nitrile intermediate to install its cyclobutane skeleton as well as three con-
tiguous stereocenters as the key transformation.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Rumphellaone A
Caryophyllane
Epoxy nitrile cyclization
Cytotoxic
Rumphellaone A (1), recently isolated from the gorgonian coral
Rumphella antipathies by Chung and co-workers as a cytotoxin with
corresponding tosylate 7 (Scheme 2).5 Ozonolytic cleavage of the
double bond of 8 afforded 9, which was then subjected to the Wit-
tig chain elongation to give 10 in a 51% overall yield from 6 after
chromatographic removal of the corresponding Z isomer from the
crude reaction product (E/Z = 8.3:1). The ester 10 was reduced to
5, and the allylic alcohol was exposed to the Sharpless asymmetric
epoxidation conditions to provide 11 with 92% enantiomeric ex-
cess, as judged by 1H NMR analyses of the corresponding (R)-
and (S)-MTPA esters. After protection of 11 as its TBS ether 12,
the product was treated with NaHMDS in refluxing toluene for
2.5 h to give a >20:1 mixture of 13 and its C1-epimer in an excel-
lent yield of 90%.6 This epoxy nitrile cyclization, when conducted at
0 °C and quenched after 40 min, gave a mixture of the starting
material 12, the desired product 13 and its C1-epimer in a ratio
of 7:1:1. This means that the highly stereoselective formation of
13 was due to its thermodynamic stability, which was supported
by our observation that a mixture of 13 and its C1 epimer con-
verged into 13 upon exposure to the same cyclization conditions
(NaHMDS in refluxing toluene).7 After protection of 13 as its TMS
ether 14, the product was reduced with DIBAL to afford the
aldehyde 15, the Horner–Wadsworth–Emmons olefination of
which gave enone 16. Removal of its two silyl protecting groups
moderate activity against CCRF-CEM tumor cells (IC50 = 12.6 lg/
mL),1 belongs to a small family of natural products known as 4,5-
seco-caryophyllanes, which consists of only four compounds
including 1 (Fig. 1). Unlike the other three members of this family,2
which are merely oxidative cleavage products of caryophyllene at
the C4–C5 double bond such as 2, rumphellaone A (1) is character-
ized by the presence of a c-lactone ring which might possibly be de-
rived biosynthetically from 2 via acid-catalyzed lactonization. In
contrast to a considerable number of synthetic studies on caryo-
phyllane-type natural products,3 no report on the synthesis of the
4,5-seco congeners has appeared in the literature, which prompted
our synthetic efforts toward this class of natural products. In this
letter, we describe the first enantioselective synthesis of 1 using
epoxy nitrile cyclization as the key transformation.
Our retrosynthetic analysis of 1 is shown in Scheme 1. We
envisaged that the keto lactone 1 would be obtainable by chain
elongation at both the C2 and C7 positions of 3. To construct the
cyclobutane ring of 3, we planned to apply Stork’s epoxy nitrile
cyclization protocol to optically active epoxide 4, which might
simultaneously be able to install the three contiguous stereogenic
centers appropriately. The epoxide 4 would be prepared by the
Sharpless asymmetric epoxidation of 5, which in turn should read-
ily be accessible from known olefinic alcohol 6.
H
H
H
According to the synthetic plan, the known compound 6,4 pre-
pared in two steps from methyl isobutylate by its allylation and
O
O
O
1
4
O
5
CO2H
subsequent reduction, was converted into nitrile
8 via the
H
H
H
caryophyllene
1
2
⇑
Corresponding author. Tel./fax: +81 22 717 8783.
E-mail address: skuwahar@biochem.tohoku.ac.jp (S. Kuwahara).
Figure 1. Structures of rumphellaone A (1) and related natural products.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.145

706
T. Hirokawa et al. / Tetrahedron Letters 53 (2012) 705–706
NMR spectral data of which showed good agreement with those
O
CN
2
H
H
H
of the natural product.1,8 The synthetic material shared the same
sign of specific rotation as the natural rumphellaone A, although
they were significantly different in the magnitude of specific rota-
CN
O
O
OR1
OR2
tion [observed data for the synthetic sample, ½a D30
ꢀ
+75.8 (c 1.11,
H
O
OR2
7
CHCl3); reported data for natural rumphellaone A, ½a D25
ꢀ
+257 (c
1
3
4
0.014, CHCl3)].9
In conclusion, the first enantioselective total synthesis of
rumphellaone A (1), featuring the epoxy nitrile cyclization of 12
to install the cyclobutane ring as well as the three contiguous ste-
reogenic center (C1, C8, and C9), has been achieved in 16 steps
from known olefinic alcohol 6. Synthesis of other 4,5-seco-caryo-
phyllanes and caryophyllane-related natural products is now
underway.
OH
CN
OH
Scheme 1. Retrosynthetic analysis of 1.
6
5
Acknowledgments
X
CN
CN
CN
c
d
f
This work was supported, in part, by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology of Japan (No. 22380064).
CHO
Y
O
OR
6: X = OH
7: X = OTs
8: X = CN
9
a
b
10: Y = CO2Et
5: Y = CH2OH
11: R = H
12: R = TBS
e
g
Supplementary data
O
H
H
H
H
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.145.
CN
CHO
k
h
j
1
OR
OTBS
OTMS
OTBS
OTMS
H
H
References and notes
OTBS
13: R = H
14: R = TMS
15
16
1. Chung, H.-M.; Chen, Y.-H.; Lin, M.-R.; Su, J.-H.; Wang, W.-H.; Sung, P.-J.
Tetrahedron Lett. 2010, 51, 6025–6027.
i
2. (a) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H. Liebigs Ann. Chem. 1984,
503–511; (b) Jakupovic, J.; Pathak, V. P.; Bohlmann, F.; King, R. M.; Robinson, H.
Phytochemistry 1987, 26, 803–807; (c) Zdero, C.; Bohlmann, F.; Anderberg, A.;
King, R. M. Phytochemistry 1991, 30, 2643–2650; (d) Quijano, L.; Vasquez-C, A.;
Ríos, T. Phytochemistry 1995, 38, 1251–1255.
3. (a) Baker, T. M.; Edmonds, D. J.; Hamilton, D.; O’Brien, C. J.; Procter, D. J. Angew.
Chem. Int. Ed. 2008, 47, 5631–5633. and references cited therein; (b) Pirrung, M.
C., ; Morehead, A. T., Jr.; Young, B. G. In The Total Synthesis of Natural Products;
Goldsmith, D., Ed.; New York: John Wiley, 2000; Vol. 11, pp 175–177.
4. Jeong, Y.; Kim, D.-Y.; Choi, Y.; Ryu, J.-S. Org. Biomol. Chem. 2011, 9, 374–378.
5. (a) Russell, G. A.; Chen, P. J. Phys. Org. Chem. 1998, 11, 715–721; (b) Yoshida, Y.;
Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55, 2183–2192.
6. (a) Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270–5272; (b) Masamune,
T.; Sato, S.; Abiko, A.; Ono, M.; Murai, A. Bull. Chem. Soc. Jpn. 1980, 53, 2895–
2904. and references cited therein.
O
O
O
H
H
H
l
m
n
OH
OH
OH
OH
H
H
H
CHO
17
18
19
CO2Et
O
O
H
H
H
o
p
O
O
OH
CO2Et
H
7. When treated with LDA/HMPA in THF at rt for 1 h, 12 was consumed completely
and gave a 5:4 mixture of 13 and its C1-epimer, which was employed for the
equilibration experiment. For the NMR spectral data of 13 and its C1-epimer, see
Supplementary data.
20
1
Scheme 2. Synthesis of 1. Reagents and conditions: (a) TsCl, Et3N, Me3NꢁHCl,
CH2Cl2, 0 °C to rt, 18 h; (b) NaCN, DMSO, 150 °C, 19.3 h; (c) O3, NaHCO3, CH2Cl2/
MeOH, ꢂ78 °C, 2 h, then Me2S, ꢂ78 °C to rt, overnight; (d) Ph3P@C(Me)CO2Et, THF,
40 °C, 20.2 h (51% from 6); (e) DIBAL, CH2Cl2, ꢂ78 to ꢂ30 °C, 4 h; (f) TBHP, Ti(Oi-
8. Physical and spectral data for 1: ½a D30
ꢀ
+75.8 (c 1.11, CHCl3) (lit.1 a 2D5
½ ꢀ +257 (c
0.014, CHCl3); IR nmax 1765 (vs), 1713 (s), 1248 (m), 1161 (m), 936 (m); 1H NMR
(400 MHz, CDCl3) d 1.04 (3H, s), 1.07 (3H, s), 1.32 (3H, s), 1.43 (1H, br t,
J = 10.3 Hz), 1.57 (1H, dd, J = 10.7, 8.7 Hz), 1.64–1.70 (2H, m), 1.82–1.93 (2H, m),
1.99–2.09 (2H, m), 2.13 (3H, s), 2.37 (2H, br t, J = 7.7 Hz), 2.54 (1H, ddd, J = 18.2,
10.0, 5.1 Hz), 2.64 (1H, ddd, J = 18.2, 9.7, 8.9 Hz); 13C NMR (100 MHz, CDCl3) d
22.5, 24.9, 25.1, 29.1, 29.9, 30.6, 30.9, 33.0, 33.5, 42.0, 44.2, 44.5, 87.2, 177.0,
208.6; HRMS (FAB) m/z calcd for C15H25O3 ([M+H]+) 253.1804, found 253.1805.
9. The enantiomeric excess of our synthetic material (1) is considered to be 92%
since that of the intermediate 11 was evaluated to be 92% by the Mosher ester
analysis and no reaction affecting the enantiomeric excess was employed in the
sequence from 11 to 1. At present, we are unable to account for the difference in
the magnitude of specific rotation, but the discrepancy might be ascribable to
the very low concentration (c 0.014) of the natural material employed for the
measurement of the specific rotation or to the presence of some impurity with a
very high rotation value either in the natural or in the synthetic sample. For 1H
and 13C NMR spectra of our synthetic material, see Supplementary data.
Pr)4,
L
-(+)-DIPT, CH2Cl2, ꢂ20 °C, 17.3 h (64% from 10); (g) TBSCl, imidazole, DMF,
0 °C to rt, 1.5 h (96%); (h) NaHMDS, PhMe, reflux, 2.5 h (90%); (i) TMSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 45 min (80%); (j) DIBAL, CH2Cl2, ꢂ20 °C to rt, 25 h (85%); (k)
MeCOCH2PO(OMe)2, NaH, DME, rt, 5 d (84%); (l) TBAF, THF, rt, 1 h (84%); (m) SO3ꢁPy,
EtN(i-Pr)2, DMSO, rt, 55 min (83%); (n) Ph3P@CHCO2Et, THF, 50 °C, 3 h (71%); (o) H2,
10% Pd/C, MeOH, rt, 1.7 h (87%); (p) CSA, CH2Cl2, rt, 15 min (73%).
followed by oxidation of the resulting diol 17 furnished 18. The
aldehyde 18 was then treated with Ph3P@CHCO2Et to give 19,
the catalytic hydrogenation of which proceeded uneventfully to
give 20. Finally, the hydroxy ester was exposed to acidic conditions
(CSA in CH2Cl2) to provide the target molecule 1, the 1H and 13C