Towards the total synthesis of tonantzitlolone - Preparation of key fragments and the complete carbon backbone

Article abstract of DOI:10.1016/j.tetlet.2004.04.056

The first synthetic advances towards the novel diterpenoid tonantzitlolone 1 are described. The key steps in the synthesis involve a chromium(II) Reformatsky reaction, a diastereoselective C₁ extension and an expeditious aldol coupling step of

Full text of DOI:10.1016/j.tetlet.2004.04.056

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4457–4460
Towards the total synthesis of tonantzitlolone––preparation of key
fragments and the complete carbon backbone
a
b
a
c
a
€
€
Rudiger Wittenberg, Christian Beier, Gerald Drager, Gerhard Jas, Christian Jasper,
Holger Monenscheina and Andreas Kirschninga,*
aInstitut f€ur Organische Chemie der Universit€at Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
bBAYER AG, Geb. 466, D-43096 Wuppertal, Germany
cCHELONA GmbH, Hermannswerder Haus 15, 14473 Potsdam, Germany
Received 4 March 2004; revised 8 April 2004; accepted 13 April 2004
Abstract—The first synthetic advances towards the novel diterpenoid tonantzitlolone 1 are described. The key steps in the synthesis
involve a chromium(II) Reformatsky reaction, a diastereoselective C1 extension and an expeditious aldol coupling step of two
advanced precursors.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In 1997, Jakupovic and Jeske isolated a new diterpenoid
from the endemic Mexican plant Stillingia sanguinolenta
with so far unknown absolute stereochemistry and
named it tonantzitlolone 1.1 Besides flexibilene 22 it is
the only 15-membered macrocyclic diterpene found in
nature so far. Two internal five- and six-membered rings
of which the latter is a d-lactol ring and an unsaturated
side chain complement important structural features of
this diterpene. Strong internal hydrogen bonds between
the hydroxy group at C-10 and the ester oxygens of the
side chain and in particular between the lactol hydroxy
group and the furan oxygen atom were noted,1 which
give the molecule a very rigid almost globular overall
structure. This compactness is further enhanced by a set
of five methyl substituents, which branch off the mac-
rocycle.
Preliminary biological evaluation3 indicated high activ-
ity and selectivity against human breast and kidney
cancer cell lines. The novel highly complex and unique
structure together with its promising biological activity
and its limited supply makes 1 an ideal candidate for
total synthesis.
Retrosynthetic analysis leads to aldehyde 3 and ketone 4
both of which are similar in size and complexity. Further
disconnection yielded twice (R)-b-hydroxy isobutyrate
5, the acylated oxazolidinone 6, and geraniol 7 as
starting materials (Scheme 1).
Starting from the commercially available isobutyrate 5
building blocks 8 and 9 were prepared straightforwardly
as reported in the literature. The free hydroxyl group in
5 was protected as TBDPS-ether, followed by reduction
of the ester.4 Oxidation was then achieved with the
reagent system diacetoxybromate(I) resin 10/TEMPO5
yielding enantiomerically pure aldehyde 8 in almost
quantitative yield.
O
H
O
O
O
HO
O
HO
H
Compound 9 was prepared by TES silylation, reduction,
and subsequent iodination using a polymer-assisted
variant6;7 of the Appel protocol (Scheme 2).8
2
1
With these building blocks in hand, we approached the
connection of both fragments via a C1-synthon. This
procedure is based on a protocol developed in our lab-
oratories.9 Thus, phosphine oxide 12 was lithiated at
Keywords: Terpene; Total synthesis; Formylation; Chromium Refor-
matsky reaction; Polymer-supported reagents.
* Corresponding author. Tel.: +49-(0)5117624614; fax: +49-(0)51176-
23011; e-mail: andreas.kirschning@oci.uni-hannover.de
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.056

4458
R. Wittenberg et al. / Tetrahedron Letters 45 (2004) 4457–4460
nesium species prepared from 9. During this reaction
McMurry or
aldol coupling
complete dissolution of the magnesium salt has to be
secured for obtaining best stereocontrol. The diaste-
reomeric ratio (syn/anti ¼ 8:1) could be determined at
the stage of the benzyl ether derivatives 16. Removal of
the primary triethylsilyl ether and polymer-assisted
oxidation of the liberated alcohol using reagent 10 as
cooxidant for TEMPO yielded aldehyde 17, which had
to serve as a coupling partner in an aldol reaction with
the ‘southern hemisphere’ 4 (Schemes 3 and 4).
olefin metathesis
OPG
4
O
4
H
O
O
8
7
8
esterification
2
OPG
2
1
O
OPG
O
HO
3
10
O
15
H
HO
OPG
OPG
1
10
1
O
15
H
O
+
4
Starting from geraniol 7, epoxyaldehyde 18 is prepared
via the asymmetric Sharpless epoxidation,11 benzylation
and subsequent ozonolysis.12 This labile aldehyde was
reacted with the a-bromoacyl oxazolidinone 6 in the
presence of CrCl2 as described by Wessjohann and
co-workers.13 This reaction directly yielded tetrahydro-
furan 19 as a mixture of diastereomers (syn/anti ¼ 3.5:1)
in one step and in moderate yield.14 Separation was
eased after O-silylation using TESCl as silylating agent.
After reductive removal of the chiral auxiliary and de-
silylation the intermediate diol was transformed into the
TBDPS-silylether 20. Oxidation of the remaining sec-
ondary alcohol functionality with Dess–Martin’s peri-
odinane15 furnished a-alkoxy ketone 21, the targeted
coupling partner for aldehyde 17.
O
4
OPG
4
M
6
+
"C1"
7
8
2
2
OPG
8
O
OPG
OPG
O
3
O
OH
OMe
5
OPG
OPG
O
O
1
1
O
10
+
O
15
O
N
O
BnO
Br
O
14
10
H
Bn
4
6
HO
After considerable experimentation16 KHMDS proved
to be the best choice for the deprotonation of 21 and the
following aldol reaction with aldehyde 17. The adduct
22 could be isolated as single diastereomer in 78%
yield.17;18
7
Scheme 1.
O
OTBDPS
O
(Ph2)P
OMe
OMe
O
8
Ph
P
OMe
OMe
12
a
Ph
NMe3 Br(OAc)2
HO
82%
10
13
OTBDPS
O
OH
CO2Me
b
c-e
OTBDPS
HO
OMe
O
PPh2 I2
86%
61%
OMOM
5
OTBDPS
11
14
15
I
OTES
I
OTES
9
9
Scheme 2.
62%
OMOM
f,g
OMOM
h,i
67%
low temperature and was reacted with aldehyde 8, which
yielded addition products 13 (syn/anti ¼ 3:1) upon
hydrolysis. This mixture of alcohols was subjected to
eliminating conditions using KOtBu and furnished the
corresponding labile O,O-ketene acetal. This interme-
diate delivered the a-hydroxy ester 14 after treatment
under asymmetric dihydroxylation conditions with AD-
mix a.10
OBn
OBn
O
OTBDPS
TESO
OTBDPS
16 (syn/anti = 8:1)
17
Scheme 3. Reagents and conditions: (a) LDA (3.5 equiv), THF,
)110 ꢁC, 10 min, then addition of 8; (b) KOtBu (1.1 equiv), THF, 0 ꢁC,
15 min, then AD-mix a, MeSO2NH2, H2O–tBuOH (1:1); (c) MOMCl,
iPrNEt2, 4-DMAP, CH2Cl2, 40 ꢁC (83%); (d) dibal-H, (3 equiv in tol-
uene), CH2Cl2, )78 ꢁC to rt (83%); (e) 10, cat. TEMPO, CH2Cl2, 50 ꢁC,
2 h (88%); (f) tBuLi (2 equiv), MgBr2–Et2O, pentane–Et2O (1.5:1),
)78 ꢁC, then 15, 30 min (82%); (g) BnBr (12 equiv), Bu4NI (14 equiv),
NaH, 70 ꢁC, 8 h (82%); (h) CSA, CH2Cl2, rt (85%); (i) 10, cat. TEMPO,
CH2Cl2, 50 ꢁC, 2 h (96%).
Further protection of the alcohol function as meth-
oxymethyl ether and a standard reduction–oxidation
sequence produced aldehyde 15, which is ideally suited
for a chelation-controlled addition of the organomag-

R. Wittenberg et al. / Tetrahedron Letters 45 (2004) 4457–4460
4459
In conclusion, we prepared key fragments 17 and 21 for
the convergent synthesis of tonantzitlolone 1 in a
straightforward manner starting from readily available
building blocks from the chiral pool. Our synthetic
approach includes reactions rarely used in natural
product synthesis such as the chromium Reformatsky
reaction, a protocol for the asymmetric acylation of
aldehydes and the use of polymer-supported reagents.
O
O
O
N
Bn
Br
BnO
, c,d
O
a,b
85%
6
O
HO
32%
18
7
O
O
O
BnO
N
BnO
OTBDPS
f
e
O
O
Work is in progress to complete the total synthesis of 1
and derivatives to establish structure–activity relation-
ships.
Bn
99%
85%
TESO
HO
H
H
20
19 (syn/anti = 3.5:1)
OMOM
BnO
O
OTBDPS
Acknowledgements
OTBDPS
OTBDPS
7
8
9
O
OBn
g
78%
OBn
O
HO
H
This research was supported by a graduate fellowship
provided by the state of Lower Saxony for R.W. and by
a Kekule scholarship for C.J. provided by the Stiftung
Stipendien-Fonds des Verbandes der Chemischen In-
dustrie. We are grateful to Dr. Jasmin Jakupovic
(AnalytiCon Discovery GmbH, Potsdam) for providing
us with details on Tonantzitlolone. Finally, we thank the
Fonds der Chemischen Industrie for general support.
21
O
H
ꢀ
22
Scheme 4. Reagents and conditions: (a) Ti(OiPr)4, tBuOOH, ())-DET,
ms, CH2Cl2, then KOtBu, BnBr, Et4NI, THF, rt (95% for two steps);
(b) O3, CH2Cl2, )78 ꢁC, PPh3, )78 ꢁC to 25 ꢁC (89%); (c) 6, CrCl2,
THF, rt, (40%); (d) TESCl, imidazole, 4-DMAP, CH2Cl2, (79%); (e)
LiBH4, THF, MeOH, 0 ꢁC, (99%), then TBAF, THF, rt followed by
TBDPSCl, imidazole, 4-DMAP, DMF, 0 ꢁC to rt (99%); (f) Dess–
Martin periodinane, CH2Cl2, rt (85%); (g) KHMDS, THF, )78 ꢁC,
then 17 (78%).
References and notes
1. Jeske, F. Ph.D. thesis, TU Berlin Germany, 1997.
ꢀ
2. (a) Herin, M.; Colin, M.; Tursch, B. Bull. Soc. Chim. Belg.
1976, 85, 707–719; (b) Kazlauskas, R.; Murphy, P. T.;
R2
H
R2
H
H
O
H
H
K
O
H
H
K
O
€
Wells, R. J.; Schonholzer, P.; Coll, J. C. Aust. J. Chem.
1978, 31, 1817–1824.
O
O
R1
O
Me
R1
3. Jakupovic, J.; Jas, J., unpublished results.
4. (a) Mulzer, J.; Mantoulidis, A.; Oehler, E. J. Org. Chem.
2000, 65, 7456–7467; (b) Paquette, L. A.; Guevel, R.;
Sakamoto, S.; Kim, I. H.; Crawford, J. J. Org. Chem.
2003, 68, 6096–6107.
H
BnO
BnO
Me
I
II
gauche
interaction
1,3-syn pentane
interaction
R2
5. (a) Sourkouni-Argirusi, G.; Kirschning, A. Org. Lett.
€
H
2000, 2, 4759–4760; (b) Brunjes, M.; Sourkouni-Argirusi,
G.; Kirschning, A. Adv. Synth. Catal. 2003, 635–642.
6. (a) Caputo, R.; Cassano, E.; Longobardo, L.; Palombo,
G. Tetrahedron Lett. 1995, 36, 167–168; (b) Caputo, R.;
Ferreri, C.; Palombo, G. Tetrahedron 1995, 51, 12337–
12350.
O
R1
Me
K
O
O
H
OBn
7. Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew.
Chem., Int. Ed. 2001, 40, 650–679.
III
8. (a) Smith, N. D.; Kocienski, P. J.; Street, S. D. A.
Synthesis 1996, 652–666; (b) Ramachandran, P. V.;
Prabhudas, B.; Pratihar, D.; Chandra, J. S.; Reddy, M.
V. R. Tetrahedron Lett. 2003, 44, 3745–3748.
Very few examples of aldol reactions comprising a Z-
enolate derived from an a-alkoxy ketone and an a-chiral
aldehyde can be found in the literature.19 By combining
the Felkin–Anh rule with the Zimmerman–Traxler
model (cf. I and cf. II) formation of the 7,8-syn,syn
diastereomer can be expected. However, ketone 22
clearly has a 7,8-anti-8,9-syn stereochemical relation-
ship, which could have originated from the anti-Felkin
transition state (cf. III). It can be assumed that transi-
tion state II suffers from severe 1,3-syn-pentane inter-
action.20 In addition, rotamer I has an unfavorable
gauche relationship. Both of these interactions are
reduced to a minimum in transition state III for which
some evidence has been collected before.21
€
9. (a) Kirschning, A.; Drager, G.; Jung, A. Angew. Chem.
1997, 109, 253–255; (b) Monenschein, H.; Drager, G.;
€
Jung, A.; Kirschning, A. Chem. Eur. J. 1999, 5, 2270–
2280.
10. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
11. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780; (b) Marty, M.; Stoeckli-Evans, H.; Neier,
R. Tetrahedron 1996, 52, 4645–4658.
12. Van Hijfte, L.; Kolb, M. Tetrahedron 1992, 48, 6393–6402.
13. Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1–36, and
references cited therein.

4460
R. Wittenberg et al. / Tetrahedron Letters 45 (2004) 4457–4460
14. When the S-configured enantiomer of 6 was employed the
corresponding Reformatsky products 19 were formed as a
diastereomeric mixture (syn/anti ¼ 1:2).
3H). 13C NMR (50 MHz, CDCl3 ¼ 77.0 ppm): d ¼ 212:5,
137.4, 135.6, 133.6, 129.6, 128.4 127.9, 127.8, 127.6, 87.6,
84.8, 73.1, 71.3, 70.2, 38.6, 35.3, 26.9, 25.8, 24.5, 20.9, 19.4.
22: colorless crystals, mp ¼ 30–35 ꢁC, MS (ESI) m=z: 1129
(M+Naþ), HRMS (CI) calcd for C68H90O9Si2 (Mþ):
15. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
23
1
16. LDA, Bu2BOTf/Et3N, Cy2BCl/Et3N, TiCl4/(iPr2)EtN,
Me2AlCl/Et3N were not successful in the enolization step.
17. Spectroscopic data of compounds 19, 21, and 22: 19:
colorless oil, IR (ATR): 2954, 2875, 1780, 1687, 1455, 1388,
1348, 1263, 1190, 1102, 1015, 967, 735, 700. MS (ESI) m/z:
1106.6123, found: 1106.6049. ½aꢀ +6.6 (c 1, CHCl3). H
D
NMR (400 MHz, CDCl3, TMS ¼ 0 ppm): d ¼ 7:71–7:60
(m, 6H), 7.44–7.15 (m, 14H), 4.70 (d, 1H, J ¼ 11:6 Hz),
4.70 (d, 1H, J ¼ 1:6 Hz), 4.68–4.65 (m, 2H), 4.58 (d, 1H,
J ¼ 11:3 Hz), 4.48 (d, 1H, J ¼ 11:3 Hz), 4.29 (d, 1H,
J ¼ 11:6 Hz), 4.17 (dd, 1H, J ¼ 9:4, 6.2 Hz), 3.92 (ddd,
1H, J ¼ 9:8, 8.6, 1.6 Hz), 3.71 (dd, 1H, J ¼ 6:5, 2.3 Hz),
3.65–3.50 (m, 1H), 3.57 (dd, 1H, J ¼ 9:5 Hz), 3.53 (d, 1H,
J ¼ 9:5 Hz), 3.46 (dd, 1H, J ¼ 9:7, 6.9 Hz), 3.22 (d, 1H,
J ¼ 9:5 Hz), 3.10 (s, 3H), 2.14–1.85 (m, 4H), 1.83–1.70 (m,
1H), 1.53–1.38 (m, 5H), 1.23–1.10 (m, 1H), 1.04 (s, 9H),
1.03 (s, 9H), 0.86 (d, 3H, J ¼ 6:7 Hz), 0.77 (d, 3H,
J ¼ 6:6 Hz), 0.81 (s, 3H), 0.71 (s, 3H). 13C NMR
(100 MHz, CDCl3 ¼ 77.0 ppm): d ¼ 212:4, 138.7, 137.0,
2 · 133.7, 133.6, 133.4, 4 · 135.6, 4 · 135.5, 2 · 129.6,
2 · 129.5, 2 · 128.8, 2 · 128.3, 2 · 128.2, 127.9, 6 · 127.6,
4 · 127.5, 127.3, 98.1, 88.1, 81.9, 80.1, 79.4, 78.2, 75.2, 72.9,
71.9, 70.3, 66.8, 55.7, 38.2, 37.5, 36.2, 34.5, 33.3, 26.9, 26.8,
25.2, 24.1, 22.6, 20.8, 2 · 19.2, 15.4, 11.3.
618 (M+Naþ), HRMS (ESI) calcd for C34H49NO6Naþ
20
D
(M+Naþ): 618.3227, found: 618.3229. ½aꢀ )17.1 (c 1,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 7:38–7.15 (m,
10H), 4.94 (dd, 1H, J ¼ 7:7, 6.5 Hz), 4.77 (ddt, 1H, J ¼ 9:1,
7.7, 3.3 Hz), 4.44 (d, 1H, J ¼ 12:0 Hz), 4.40 (d, 1H,
J ¼ 12:0 Hz), 4.18 (dd, 1H, J ¼ 8:8, 7.7 Hz), 4.12 (dd,
1H, J ¼ 8:8, 3.3 Hz), 3.74–3.66 (m, 2H), 3.35 (dd, 1H,
J ¼ 9:2, 7.3 Hz), 3.15 (dd, 1H, J ¼ 13:4, 3.3 Hz), 2.72 (dd,
1H, J ¼ 13:4, 9.1 Hz), 2.03–1.89 (m, 2H), 1.74–1.61 (m,
2H), 1.38 (s, 3H), 1.32 (s, 3H), 1.14 (s, 3H), 0.94 (t, 9H,
J ¼ 8:0 Hz), 0.67–0.56 (m, 6H). 13C NMR (50 MHz,
CDCl3): d ¼ 176:7, 152.5, 138.5, 135.6, 129.4, 128.8,
128.1, 127.5, 127.2, 127.1, 84.3, 80.1, 77.2, 73.2, 73.0,
66.1, 57.3, 48.7, 37.8, 36.3, 26.0, 20.5, 20.1, 19.4, 6.9, 5.2.
21: colorless oil, IR (NaCl): 3070, 2961, 2858, 1732, 1473,
1112, 825, 740, 702. MS (EI, 85 ꢁC) m=z (rel. intensity): 487
(M)tBu, 25.7), 395 (90), 331 (12), 269 (21), 239 (26), 199
(59), 139 (62), 91 (100). MS (ESI) m=z: 567 (M+Naþ),
HRMS (EI) calcd for C30H35O4Si (M)tBu)þ: 487.2305,
found: 487.2306. 1H NMR (400 MHz, CDCl3 ¼ 7.26 ppm):
d ¼ 7:75–7.65 (m, 4H), 7.46–7.28 (m, 11H), 4.59 (d, 1H,
J ¼ 11:8 Hz), 4.54 (d, 1H, J ¼ 11:8 Hz), 4.47 (d, 1H,
J ¼ 18:9 Hz), 4.42 (d, 1H, J ¼ 18:9 Hz), 4.09 (dd, 1H,
J ¼ 9:8, 5.6 Hz), 3.55 (d, 1H, J ¼ 9:5 Hz), 3.30 (d, 1H,
J ¼ 9:5 Hz), 2.20–2.12 (m, 1H), 1.86–1.76 (m, 2H), 1.63–
1.51 (m, 1H), 1.34 (s, 3H), 1.06 (s, 9H), 0.90 (s, 3H), 0.78 (s,
18. The relative stereochemistry at C-7 to C-9 in adduct 22
was determined after 8,10-syn reduction of the keto group
followed by protection of the 8,10-diol as the correspond-
ing acetonide. H,H-Coupling constants in the six-mem-
bered ring and NOE-correlations served as diagnostic
tools for this purpose.
19. Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223.
20. Hoffmann, R. W. Angew. Chem. 2000, 112, 2134–2150.
21. (a) Roush, W. R. J. Org. Chem. 1991, 56, 4151–4157; (b)
Gennari, C.; Vieth, S.; Comotti, A.; Vulpetti, A.; Good-
mann, J. M.; Paterson, I. Tetrahedron 1992, 48, 4439–
4458.