32
LETTER
Enantioselective First Total Syntheses of 2-(Formylamino)trachyopsane and
ent-2-(Isocyano)trachyopsane via a Biomimetic Approach
2-(Formylamino)-andent-2 (IsSrikrishna,*
A.
ocyano)trachyopsane
G. Ravi, D. R. C. Venkata Subbaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 10 July 2008
5
H
1
2
3
4
5
R
Key words: natural products, marine sesquiterpenes, enantioselective synthesis, biomimetic synthesis, acid-catalysed rearrangement
R = NHCHO
R = NHCONHCH2CH2Ph
R = H (trachyopsane)
R = NCS
R = NC
Earlier, it was hypothesized4 (Scheme 1) that the pupukeanane and neopupukeane skeletons are derived from
amorphane via the twistane cation 6 by either the C3–C4
bond or C1–C10 bond migration, respectively, which is
further supported by the co-occurrence of these compounds. It has been further extrapolated and postulated5
that the allopupukeanane 9 can be formed by a C1–C2
bond migration of 9-pupukeanyl cation 10. Herein, we
propose that trachyopsanes 1–5 are biogenetically derived
SYNLETT 2009, No. 1, pp 0032–0034xx. 208
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087382; Art ID: D26408ST
© Georg Thieme Verlag Stuttgart · New York
3
10
2
7
8
1
9
tricyclo[4.3.1.03,8]decane
X
CN
X
Y
During a search for biologically active antitumor agents
from marine sources, Patil and co-workers found an extract of a sponge collected in Palau, Axinyssa aplysinoides
Dendy 1922, to be active, and bioassay-guided fractionation revealed1 that the bioactivity was associated with the
metabolites 1 and 2 (Figure 1). Structures of 1 (existing as
a 1:3 mixture of rotamers) and 2 were established, on the
basis of single crystal X-ray diffraction analysis, as 2(formylamino)trachyopsane and N-phenethyl-N¢-2-trachyopsanylurea, respectively. The marine sesquiterpenes
trachyopsanes (3), coexist with pupukeananes, contain an
interesting tricyclo[4.3.1.03,8]decane framework, whose
first member, 2-isothiocyanatotrachyopsane 4, was
reported2 in 1989 by the research groups of Faulkner and
Clardy from Palauan sponge Trachyopsis aplysinoides
along with cadinane and pupukeanane derivatives.
Subsequently3 in 1996, during their investigations on the
antifouling compounds from Japanese marine invertebrates, Fusetani and co-workers reported the bioassayguided isolation of 2-isocyanotrachyopsane 5 from the
nudibranch Phyllidia varicosa. Indeed, 2-isocyanotrachyopsane 5 exhibited good antifouling activity (IC50 0.33 mg/
mL).3 Although relative structures were assigned, the absolute configuration has not yet been assigned for any trachyopsanes.
6
4
Y
pupukeananes
(X, Y = H, NC, SCN
etc.)
neopupukeananes
(X, Y = H, SCN)
isocyanoallopupukeanane
Figure 1
5
H
3
4
10
1
6
8
6
amorphane
(1,10)
(3,4)
pupukeananes
8
7
1,3-H shift
10
1,3-H shift
neopupukeananes
allopupukeanane
11
9
trachyopsanes
1–5
Scheme 1
from neopupukananes via the C2–C4 bond migration of
neopupukean-4-yl cation 11.
On the basis of the above-speculated biogenesis of trachyopsanes, it was contemplated that a suitably substituted
neopupukeanane (to generate a carbonium ion at C-4 po-
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Abstract: A biomimetic rearrangement of an isotwistane to a tricyclo[4.3.1.03,8]decane has been employed as the key step for the
enantioselective first total syntheses of the marine sesquiterpenes 2(formylamino)trachyopsane and ent-2-(isocyano)trachyopsanes ascertaining the biogenetic relationship between the marine sesquiterpenes neopupukeananes and trachyopsanes.
2-(Formylamino) and ent-2-(Isocyano)trachyopsane
sition, ca. 11) can serve as a precursor for trachyopsanes
1–5. In continuation of our interest in the enantiospecific
synthesis of tricyclic marine sesquiterpenes, we have explored the biomimetic conversion of neopupukeananes to
trachyopsanes for the enantioselective first6 total syntheses of 2-formylaminotrachyopsane 1 and 2-isocyanotrachyopsane 5, which is the subject of this communication.
regioselective rearrangement of the alcohol 17 by employing camphorsulfonic acid (CSA). Thus, refluxing a
benzene solution of the hydroxyketone 17 with 50 mol%
of CSA furnished trachyops-2(14)-en-7-one 18 in 87%
yield in a highly regioselective manner, whose structure
was established from its spectral data.
The synthetic sequence is depicted in Scheme 2. To begin,
carvone (12) was converted into neopupukean-11(13)-en4,10-dione (13) following an protocol developed earlier.7
Thus, reaction of carvone (12) with lithium hexamethyldisilazide (LiHMDS) and methyl methacrylate furnished
the bicyclo[2.2.2]octanecarboxylate 14 via intermolecular
Michael reaction followed by intramolecular Michael addition reactions. Reaction of the diazoketone 15, derived
from the ester 14, with rhodium acetate furnished the isotwistane dione 13 via regioselective C–H insertion of the
intermediate rhodium carbenoid. Exploiting the difference in steric crowding of the two ketones in 13, the C-4
ketone was regio- and stereoselectively reduced to the alcohol 16 by reacting with sodium borohydride in methanol, which on hydrogenation with 10% palladium over
carbon as the catalyst furnished the key intermediate 17.
The pivotal biomimetic rearrangement of the alcohol 17 to
a trachyopsane was investigated with a variety of Lewis
and Brønsted acids.8 We were pleased to achieve a highly
O
a
O
65%
O
92%
X
O
14 X = OMe
15 X = CHN2
12
c
O
b
13
d 89%
H
O
O
O
f
e
87%
100%
HO
18
HO
17
89% g or h
H
H
k
X
94%
HN
HN
X
19 X = COMe
20 X = CHO
CHO
21 X = SCH2CH2S
1 X = H2
92%
CN
j 100%
Next, incorporation of an amine group at the C-2 position
was explored. Ritter reaction of the olefin 18 with sulfuric
acid and acetonitrile in acetic acid furnished 2-acetylaminotrachyopsan-7-one (19, 1:4 mixture of rotamers) in
90% yield. In a similar manner, reaction of the olefin 18
with sulfuric acid and cyanotrimethylsilane9 in acetic acid
furnished 2-formylaminotrachyopsan-7-one (20, 1:4 mixture of rotamers) in 89% yield. Reaction of the ketone 20
with ethanedithiol in the presence of a substoichiometric
amount of iodine furnished the thioketal 21, which on desulfurisation with Raney nickel in refluxing ethanol furnished 2-formylaminotrachyopsane (–)-1 (1:3 mixture of
rotamers as in natural product). The synthetic compound
1 exhibited the optical rotation and spectral data identical
to that of natural 2-formylaminotrachyopsane (–)-1, establishing the absolute configuration of the natural product.
Dehydration of 2-formylaminotrachyopsane (–)-1 with ptoluenesulfonyl chloride and pyridine furnished 2-isocyanotrachyopsane (–)-5 in 92% yield. Synthetic compound (–)-5 exhibited spectral data identical to those
reported for 2-isocyanotrachyopsane (+)-5, however, it
was found to be the enantiomer of the natural compound.
In conclusion, we have developed efficient enantioselective first total syntheses of marine sesquiterpenes 2formylaminotrachyopsane (1) and 2-isocyanotrachyopsane (5), employing a biomimetic rearrangement of a
neopupukeanane into a trachyopasane as the key step. In
the present sequence starting from the known dione 13
[available from (R)-carvone in 4 steps in >50% yield], 1
and 5 were obtained in six and seven steps in overall
yields of 65% and 60%, respectively. It is worth noting
that the two natural trachyopsanes 1 and 5, isolated from
marine sources (one from a sponge and the other from a
nudibranch), have enantiomeric skeletons.
Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H NMR, 13C NMR,
and HRMS) consistent with their structures.
H
i
O
16
33
5
Scheme 2 Reagents and conditions: (a) LiN(TMS)2, hexane,
CH2=C(Me)COOMe; (b) i. NaOH, MeOH–H2O, reflux; ii. (COCl)2,
C6H6; iii. CH2N2, Et2O; (c) Rh2(OAc)4, CH2Cl2;7 (d) NaBH4, MeOH,
0 °C, 10 min; (e) H2 (1 atm), 10% Pd/C, EtOAc, 2 h; (f) CSA (50
mol%), C6H6, reflux, 20 h; (g) concd H2SO4 (10 equiv), MeCN (5
equiv), AcOH, 0 °C to r.t., 24 h; (h) concd H2SO4 (10 equiv), TMSCN
(5 equiv), AcOH, –10 °C to r.t., 24 h; (i) (CH2SH)2, I2, CH2Cl2, 0 °C
to r.t., 24 h; (j) Raney Ni, EtOH, reflux, 2 h; (k) TsCl, pyridine, 0 °C
to r.t., 3 h.
Selected Spectral Data for (1S,3S,5S,6S,8R)-5-Isopropyl-8methyl-2-methylenetricyclo[4.3.1.03,8]decan-7-one (18)
[a]D23 –140.7 (c 1.5, CHCl3). IR (neat): nmax = 1716, 1455, 1371,
1188, 1177, 1134, 1074, 880 cm–1. 1H NMR (400 MHz, CDCl3):
d = 4.97 (1 H, s, C=CH2), 4.75 (1 H, s, C=CH2), 2.72 (1 H, br s),
2.59 (1 H, br s), 2.42 (1 H, d, J = 6.5 Hz), 2.10–1.97 (1 H, m), 1.90–
1.80 (2 H, m), 1.75–1.44 (6 H, m), 1.07 (3 H, s, t-CH3), 0.86 [3 H,
d, J = 6.6 Hz, CH(CH3)2] and 0.83 [3 H, d, J = 6.8 Hz, CH(CH3)2].
13
C NMR (100 MHz, CDCl3): d = 217.6 (C, C=O), 157.0 (C,
C=CH2), 104.4 (CH2, C=CH2), 54.5 (C), 51.0 (CH), 50.2 (CH), 49.1
(CH), 48.2 (CH2), 43.6 (CH), 41.4 (CH2), 32.8 (CH), 28.6 (CH2),
20.3 (CH3), 19.6 (CH3), 18.4 (CH3). HRMS: m/z calcd for C15H23O2
[M + H]: 219.1749; found: 219.1745.
Synlett 2009, No. 1, 32–34
© Thieme Stuttgart · New York
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LETTER
LETTER
A. Srikrishna et al.
(1S,2R,3R,5S,6S,8R)-2-Formylamino-5-isopropyl-2,8-dimethyltricyclo[4.3.1.03,8]decan-7-one (20)
A 1:4 mixture of rotamers; [a]D24 –134.9 (c 7.4, CHCl3). IR (neat):
nmax = 3302, 2751, 1715, 1667, 1530, 1456, 1387, 1255 cm–1. 1H
NMR (400 MHz, CDCl3): d (peaks for the major rotamer) = 7.99 (1
H, s, CHO), 5.96 (1 H, br s, NH), 2.51 (1 H, br s), 2.47 (1 H, d, J =
6.9 Hz), 2.30 (1 H, br s), 2.20 (1 H, dt, J = 8.8, 3.6 Hz), 2.20–1.75
(3 H, m), 1.69 (1 H, q, J = 9.2 Hz), 1.61 (3 H, s, t-CH3), 1.51 (1 H,
d, J = 8.8 Hz), 1.30–1.20 (2 H, m), 1.06 (3 H, s, t-CH3), 0.87 [3 H,
d, J = 6.4 Hz, CH(CH3)2], 0.82 [3 H, d, J = 6.7 Hz, CH(CH3)2];
d (important peaks for the minor rotamer) = 8.25 (1 H, d, J = 12.1
Hz, CHO), 1.58 (3 H, s, t-CH3), 1.10 (3 H, s, t-CH3). 13C NMR (100
MHz, CDCl3): d (peaks for the major rotamer) = 217.2 (C, C=O),
160.2 (CH, HC=O), 66.5 (C), 55.7 (CH), 54.4 (C), 51.7 (CH), 47.7
(CH), 44.8 (CH), 44.4 (CH2), 35.9 (CH2), 33.2 (CH), 26.3 (CH2),
21.0 (CH3), 20.2 (CH3), 19.3 (CH3), 18.6 (CH3); d (peaks for the minor rotamer) = 216.2 (C, C=O), 163.7 (CH, HC=O), 65.4 (C), 57.3
(CH), 54.6 (C), 51.6 (CH), 47.6 (CH), 47.0 (CH), 44.0 (CH2), 36.0
(CH2), 33.2 (CH), 26.33 (CH2), 23.1 (CH3), 20.2 (CH3), 18.8 (CH3).
HRMS: m/z calcd for C16H25NO2 + Na [M + Na]: 286.1783; found:
286.1771.
(1S,2R,3R,5S,6R,8R)-2-Formylamino-5-isopropyl-2,8dimethyltricyclo[4.3.1.03,8]decane
A 1:3 mixture of rotamers [2-(formylamino)trachyopsane (1)]; mp
108–110 °C; [a]D23 –68.1 (c 2.7, MeOH); lit.1 –67.5 (c 0.56,
MeOH). IR (thin film): nmax = 3292 (NH), 2942, 2863, 1681, 1661,
1532, 1470, 1455, 1386, 1263, 1221 cm–1. 1H NMR (400 MHz,
CDCl3): d (peaks for the major rotamer) = 7.96 (1 H, d, J = 1.5 Hz,
HC=O), 5.40 (1 H, br s, NH), 2.29 (1 H, m), 2.00–1.65 (5 H, m),
1.52 (3 H, s, t-CH3), 1.50–1.25 (3 H, m), 1.25–1.10 (4 H, m), 0.96
(3 H, s, t-CH3), 0.86 (3 H, d, J = 6.4 Hz, CH(CH3)2], 0.84 [3 H, d,
J = 6.7 Hz, CH(CH3)2]; d (important peaks for the minor rotamer) =
8.21 (1 H, d, J = 12.4 Hz, HC=O), 6.00 (1 H, br s, NH), 2.03 (1 H,
m), 1.47 (3 H, s, t-CH3), 0.98 (3 H, s, t-CH3), 0.86 [3 H, d, J = 6.4
Hz, CH(CH3)2], 0.84 [3 H, d, J = 6.7 Hz, CH(CH3)2]. 13C NMR (100
MHz, CDCl3): d (peaks for the major rotamer) = 160.1 (CH,
HC=O), 67.6 (C), 51.4 (CH), 46.6 (CH), 45.2 (CH), 45.1 (CH2),
38.9 (C), 37.5 (CH2), 34.6 (CH2), 31.8 (CH), 31.5 (CH), 27.8 (CH3),
25.0 (CH2), 21.6 (CH3), 20.9 (CH3), 19.7 (CH3); d (peaks for the minor rotamer) = 163.6 (CH, HC=O), 66.5 (C), 53.5 (CH), 47.4 (CH),
46.7 (CH), 44.6 (CH2), 39.4 (C), 37.5 (CH2), 34.8 (CH2), 31.8 (CH),
31.4 (CH), 27.3 (CH3), 25.1 (CH2), 24.4 (CH3), 21.6 (CH3), 20.9
(CH3).
(1S,2R,3R,5S,6R,8R)-2-Isocyano-5-isopropyl-2,8-dimethyltricyclo[4.3.1.03,8]decane (2-Isocyanotrachyopsane 5)
[a]D22 –74.5 (c 1.1, CHCl3); lit.1 +74.4 (c 0.23, CHCl3). IR (neat):
n max = 2125 (NC), 1470, 1455, 1384, 1369, 1173, 1153 cm–1 .
1
H NMR (400 MHz, CDCl3): d = 2.26 (1 H, br d, J = 11.7 Hz), 2.16
Synlett 2009, No. 1, 32–34
© Thieme Stuttgart · New York
(1 H, br s), 1.99 (1 H, br s), 1.92 (1 H, br s), 1.77 (1 H, ddd, J = 10.8,
6.3, 3.5 Hz), 1.70 (1 H, ddd, J = 10.3, 6.0, 2.7 Hz), 1.55 (3 H, br s,
t-CH3), 1.50–1.20 (4 H, m), 1.29–1.24 (1 H, m), 1.24–1.22 (2 H, m),
1.12–1.00 (1 H, m), 1.06 (3 H, s, t-CH3), 1.02–1.00 (1 H, m), 0.86
[3 H, d, J = 7.5 Hz, CH(CH3)2], 0.83 [3 H, d, J = 6.7 Hz, CH(CH3)2].
13
C NMR (100 MHz, CDCl3): d = 152.1 (C, NC), 70.8 (C, C-2), 53.5
(CH), 47.3 (CH), 46.8 (CH), 45.3 (CH2), 39.3 (C), 37.2 (CH2), 34.2
(CH2), 31.8 (CH), 31.2 (CH), 27.3 (CH3), 24.8 (CH2), 22.5 (CH3),
21.5 (CH3), 20.8 (CH3).
Acknowledgment
We thank Alan Freyer of GSK Pharmaceutical Co. for providing the
copies of the 1H NMR and 13C NMR spectra of natural product
2-formylaminotrachyopsane, and the CSIR, New Delhi for the
award of research fellowship to G. R.
References and Notes
(1) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Bean, M. F.;
Faucette, L.; Johnson, R. K.; Haltiwanger, R. C.; Eggleston,
D. S. J. Nat. Prod. 1997, 60, 507.
(2) (a) He, H. Y.; Faulkner, D. J.; Shumsky, J. S.; Hong, K.;
Clardy, J. J. Org. Chem. 1989, 54, 2511. (b) He, H. Y.;
Salvi, J.; Catalos, R. F.; Faulkner, D. J. J. Org. Chem. 1992,
57, 3191.
(3) Okino, T.; Yoshimura, E.; Hirota, H.; Fusetani, N.
Tetrahedron 1996, 52, 9447.
(4) Karuso, P.; Poiner, A.; Scheuer, P. J. J. Org. Chem. 1989, 54,
2095.
(5) Fusetani, N.; Wolstenhohne, H. J.; Matsunaga, S.; Hirota, H.
Tetrahedron Lett. 1991, 32, 7291.
(6) So far there is no report in the literature on the total synthesis
or model studies of any racemic or optically active
trachyopsanes.
(7) Srikrishna, A.; Gharpure, S. J. Chem. Commun. 1998, 1589.
(8) The rearrangement was attempted with BF3·OEt2, BF3·OEt2
in the presence of TFA, TFA, MeSO2OH, and concentrated
H2SO4; in all these experiments either starting material
recovered or a complex mixture was produced. Reaction
with formic acid generated the formate ester of the alcohol
17, whereas PTSA (1 equiv) in MeCN produced a mixture of
the acetate and tosylates of the alcohol 17 along with the
rearranged product 18. Significant amount (50–60%) of
rearranged product 18 was formed when the reaction was
carried out with PTSA (1 equiv) in refluxing benzene.
(9) Chen, H. G.; Goel, O. P.; Kesten, S.; Knobelsdorf, J.
Tetrahedron Lett. 1996, 37, 8129.
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