Diastereocontrol in the synthesis of models of rings C and D of phorbol: Directing effect of an ether substituent on lithium carbenoid mediated cyclopropanation

Article abstract of DOI:10.1002/1521-3773(20010618)40:12<2311::AID-ANIE2311>3.0.CO;2-T

The diastereocomplementarity of halo- and alkylcarbenes (paths a and b, respectively) was shown in the cyclopropanation reaction of 1. The conversion of 1 into 7,7-dimethylbicyclo[4.1.0]heptan-1,2-diols (±)-2 and (±)-3 represents an important transformati

Full text of DOI:10.1002/1521-3773(20010618)40:12<2311::AID-ANIE2311>3.0.CO;2-T

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Herein we report the synthesis of 1S(R),2R(S)-dihydroxy-
7,7-dimethyl-(6R(S))-bicyclo[4.1.0]heptane (6), as a model of
rings C and D of phorbol (1), by means of a stereoselective
cyclopropanation of an intermediate enol ether 7, which in
Diastereocontrol in the Synthesis of Models of
Rings C and D of Phorbol: Directing Effect of
an Ether Substituent on Lithium Carbenoid
Mediated Cyclopropanation**
SBn
BnS
O
Michael G. B. Drew, Laurence M. Harwood,*
O
OCH3
O
OCH3
OCH3
O
Â
Antonio J. Macías-Sanchez, Richard Scott,
O
O
H
R. M. Thomas, and Daniel Uguen
H
H
H
b), c)
d)
a)
O
O
O
OH
O
Phorbol esters is a term used collectively to describe a
family of structurally related, biologically active tetracyclic
diterpenes.[1] Phorbol (1), the parent compound of this class of
diterpenes, was first isolated in 1934
O
H
H
O
O
O
5
3
4
Scheme 1. Reagents and conditions: a) 1900 MPa, CH2Cl2, 15 h, 65%;
b) H2 (1.5 MPa), EtOAc, Pd/BaSO4, 83%; c) NaOMe cat., MeOH, room
temperature, 84%; d) HgCl2, aq. CH3CN, 508C, 8 days, 58%.
by Bohm et al.[2] as a hydrolysis
R1
R2
product of Croton tiglium oil. Its
core structure was elucidated by
X-ray crystallography by Hecker
and co-workers in 1967.[3] Probably
the most important physiological
property of the phorbol esters is
their capacity to act as tumor pro-
moters;[4] for example, tetradodeca-
noyl phorbol acetate (TPA; 2) is the
most potent tumor promoter known
D
C
turn would be obtained from methyl 2-oxocyclohexanecar-
boxylate (8) (Scheme 2).
H
H
H
OH
B
A
OR1
OH
OH
OR2
OH
OH
O
O
1 R1 = R2 = OH
CO2CH3
2 R1 = OCO(CH2)12CH3
H
R2 = OAc
6
7
8
Scheme 2. Retrosynthetic analysis of the synthesis of model compound 6
from methyl 2-oxocyclohexanecarboxylate (8).
to man, being active at levels of 0.02 mmol.[5] The origin of
such activity was identified in 1982 when Castagna et al.[6]
showed TPA (2) bound to the ubiquitous enzyme protein
kinase C.
The complex polycyclic structure of phorbol, together with
an intense interest in structure ± activity relationship studies
to map the basis of the tumor-promotion activity have fueled
extensive efforts towards establishing efficient synthetic
routes to phorbol (1) and its derivatives.[7]
The approach adopted by our group has involved the
intramolecular Diels ± Alder reaction of 3, which bears a furan
system and a suitable dienophile fragment. In one step, we
obtained the ABC tricyclic core 4, which possessed strategi-
cally situated functionality for further elaboration.[8] Addi-
tional transformations of the cycloadduct led to a b-ketoester
functionality on ring C (compound 5),[9] which allows us to
tackle the construction of the bicyclo[4.1.0]heptane moiety of
rings C and D in phorbol (1; Scheme 1).
In the initial part of the study, b-ketoester 8 was treated
with trimethyl orthoformate and 10-camphorsulfonic acid (10-
CSA) in MeOH, and heated at reflux for 16 h to furnish the
dimethyl acetal 9. This compound was transformed into the
methyl enol ether 10 under kinetic conditions by treatment of
compound 9 with two equivalents of lithium diisopropylamide
(LDA) in THF at 408C (Scheme 3).
OMe
OMe
b)
a)
OMe
8
CO2CH3
10
CO2CH3
9
OTBDMS
O
OH
O
d)
c)
CO2CH3
CO2CH3
12
11
OTBDMS
OTBDMS
O
Â
[*] Prof. L. M. Harwood, Prof. M. G. B. Drew, Dr. A. J. Macías-Sanchez,
6
OTBDMS
e)
f)
1
Dr. R. Scott
Department of Chemistry, University of Reading
Whiteknights, Reading RG6 6AD (UK)
Fax : (‡44)1189-316-782
15
13
E-mail: l.m.harwood@reading.ac.uk
OH
O
Prof. D. Uguen
Â
Ecole de Chimie, des Polym›res et des MatØrieaux
g)
O
OH
Á
Laboratoire de Synthese Organique
25 rue Becquerel, 67087 Strasbourg (France)
14
Dr. R. M. Thomas
Astra-Zeneca
Silk Road Business Park
Macclesfield SK102NA (UK)
Scheme 3. Synthesis of enol ether 15 from either b-ketoester 8 or adipoin
(14). Reagents and conditions: a) HC(OMe)3, 10-CSA, MeOH, reflux,
16 h, 99%; b) LDA (2 equiv), THF, 408C, 1 h, 92%; c) 1. DMDO (0.1m
solution in acetone), CH2Cl2, 10 min; 2. 10-CSA, acetone, 30 min, 70%;
d) TBDMSCl, imidazole, DMAP (cat.), CH2Cl2, room temperature, 2 h,
91%; e) dimethyl sulfoxide, H2O, NaCl, 1308C, 30 min, quant.;
f) TBDMSOTf, Et3N, CH2Cl2, room temperature, 3 h, 83%; g) TBDMSCl,
imidazole, DMAP (cat.), CH2Cl2, room temperature, 2 h, quant.
[**] We thank Mr. A. W. Jahans for technical assistance. A.J.M.-S. thanks
the Secretaria de Estado de Universidades, Investigacion y Desarrollo
(SEUID; Spanish funding body) for a postdoctoral fellowship. R.S.
thanks Astra ± Zeneca for a research studentship.
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To accomplish the incorporation of the secondary hydroxy
group, a consecutive two-step sequence was conceived in
which an epoxidation of the enol ether 10 with dimethyldiox-
irane (DMDO)[10] was followed by an acidic workup to allow
the formation of the a-hydroxyketone 11. Subsequently, the
secondary hydroxy group was protected by treatment with
tert-butyldimethylsilyl chloride (TBDMSCl), imidazole, and a
catalytic amount of 4-dimethylaminopyridine (DMAP), to
yield compound 12 (Scheme 3).
The b-ketoester function in 12 was decarboxylated by the
application of a variation of the procedure of Krapcho,[11] to
give compound 13. An alternative and convenient short route
to 13 was subsequently employed from this point. Treatment
of the commercially available 2-hydroxycyclohexanone dimer
(adipoin; 14) with TBDMSCl, imidazole, and a catalytic
amount of DMAP in CH2Cl2 at room temperature, provided
the protected hydroxyketone 13 in a quantitative yield. To
proceed to the critical cyclopropanation step, compound 13
was transformed into the TBDMS enol ether 15 by treatment
with TBDMSOTf (OTf ˆ trifluoromethanesulfonate) and
triethylamine at room temperature in dichloromethane for
three hours (Scheme 3).[12]
Initially, the construction of the dimethylcyclopropane
moiety was addressed by reaction of compound 15 with
dibromocarbene[13] and further transformation of the resulting
dibromocompound with a homocuprate,[14] to yield the
dimethylated compounds 18 and 19. Thus, when one equiv-
alent of bromoform was added dropwise for one hour to a
stirred slurry of compound 15 and potassium tert-butoxide in
anhydrous pentane at 108C, dibromo compounds 16 and 17
were obtained (Scheme 4). Both compounds showed analo-
gous patterns in their 1H and 13C NMR spectra, but the signals
at d ˆ 4.07 (dd, J ˆ 4.3 Hz, 11.5 Hz, 1H; CHOTBDMS) in
compound 16 and at d ˆ 4.13 (t, J ˆ 9.1 Hz, 1H;
CHOTBDMS) in compound 17 suggested that they were
epimers at C2. Compound 16 proved to be thermally unstable
and after one week at room temperature was completely
degraded. Nevertheless, compound 17 was stable under the
same conditions. This permitted a pure sample of compound
17 to be obtained, a difficult task by chromatography.
Compound 17 furnished crystals suitable for X-ray crystallo-
graphic analysis,[15] which established the structure of com-
pound 17 as 7,7-dibromo-1S(R),2S(R)-di-tert-butyldimethylsi-
lyloxy-(6R(S))-bicyclo[4.1.0]heptane. Therefore, the major
compound 16 was concluded to be the epimeric 7,7-dibro-
mo-1S(R),2R(S)-di-tert-butyldimethylsilyloxy-(6R(S))-bicy-
clo[4.1.0]heptane.
Treatment of a mixture of 16 and 17 with four equivalents of
lithium dimethylcuprate at 238C, and then with MeI at
638C, yielded the corresponding gem-dimethyl compounds
18 and 19 (Scheme 4). The stereochemistry in compound 18
was established by NOE analysis, which in turn served to
confirm the stereochemistry of the major dibromo adduct 16.
An alternative and direct route to compound 19 was found
when the enol ether 15 was treated with the lithium carbenoid
generated from nBuLi and 2,2-dibromopropane[16] in pentane
at 788C.[17] Compound 19 was furnished as the sole adduct.
The separate treatment of 19 and 18 with tetra-n-butyl
ammonium fluoride in THF yielded the epimeric diols 6 and
20 in yields of 39% and 53%, respectively.
The behavior of the dibromocarbene and that of the lithium
carbenoid derived from 2,2-dibromopropane are different.
For dibromocarbene, steric hindrance seems to play a major
role in determining the course of the approach of the reagent
to the double bond, to yield 16, with a cyclopropane ring trans
to the secondary silyl ether group, as the major product. On
the other hand, the reaction with the lithium carbenoid only
yields a single product, compound 19, whose cyclopropane
ring is cis to the secondary silyl ether group. This suggests a
directing effect from the oxygen in the ether functionality on
the cyclopropanation reaction. This kind of effect has been
reported previously in Simmons ± Smith type reactions,[18] but,
to our knowledge, has not been described previously for
lithium carbenoids.
OTBDMS
OTBDMS
OTBDMS
OTBDMS
Br
OTBDMS
OTBDMS
2
1
a)
Br
+
6
Br
Br
H
H
15
c)
16 (53%)
17 (19%)
b)
19
In summary, we have converted a b-ketoester into a
hydroxydimethylcyclopropane derivative with diastereocon-
trol, by means of a protocol that may be applied in our
synthetic strategy towards phorbol derivatives. We have also
shown an interesting diastereocomplementarity of halocar-
benes and alkylcarbenes in this process.
(21%)
(45% based
on recovery
of 15)
OTBDMS
OTBDMS
OTBDMS
OTBDMS
+
H
H
d)
19 (6%, from 17)
18 (37%, from 16)
OH
OH
OH
OH
Experimental Section
8
Selected spectroscopic data: 20: 1H NMR (250 MHz, CDCl3, 258C, TMS):
d ˆ 3.89 (m, 1H; CHOTBDMS), 2.90 ± 2.70 (2H; -OH) 1.98 ± 1.83 (1H;
5-H), 1.69 ± 1.42 (4H; 3-H, 3'-H, 4-H, 4'-H), 1.39 ± 1.05 (m, 1H; 5'-H), 1.21
(s, 3H; CH3), 1.00 (s, 3H; CH3), 0.81 (dd, J ˆ 2.5, 9.5 Hz, 1H; CH);
13C NMR (62.5 MHz, CDCl3, 258C, TMS): d ˆ 65.20, 60.65, 31.22, 27.78,
23.38, 22.75, 19.14, 18.64, 16.04. 6: 1H NMR (250 MHz, CDCl3, 258C,
TMS): d ˆ 4.38 (dd, J ˆ 7.9, 10.6 Hz, 1H; CHOTBDMS), 2.18 ± 1.89 (2H;
3-H, 5-H) 1.55 (m, 1H; 4-H), 1.28 ± 1.13 (3H; 3'-H, 4'-H, 5'-H), 1.23 (s, 3H;
CH3), 1.17 (s, 3H; CH3), 0.98 (dd, J ˆ 3.3, 10.0 Hz, 1H; CH); 13C NMR
d)
9
H
H
(39%)
6
20 (53%)
Scheme 4. Synthesis of the epimeric diols 6 and 20 from the enol ether 15.
Reagents and conditions: a) CHBr3 (1 equiv, dropwise over 1 h), tBuOK,
pentane, 108C !room temperature, 3 h; b) Me2CuLi (4 equiv), Et2O,
238C, 3 h, then MeI, 638C, 1 h; c) (CH3)2CBr2, nBuLi, pentane, 788C
(3 h), 788C !room temperature (14 h); d) nBu4NF, THF, reflux, 2 h.
2312
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Angew. Chem. Int. Ed. 2001, 40, No. 12

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(62.5 MHz, CDCl3, 258C, TMS): d ˆ 76.31, 62.70, 31.84, 31.58, 25.65, 24.17,
Constructing Tricyclic Compounds Containing
a Seven-Membered Ring by Ruthenium-
Catalyzed Intramolecular [5‡2]
Cycloaddition**
22.71, 19.04, 16.37.
Received: December 18, 2000 [Z16294]
Barry M. Trost* and Hong C. Shen
[1] F. J. Evans, C. J. Soper, Lloydia 1978, 41, 193.
[2] R. Bohm, B. Flaschenträger, L. Lendle, Arch. Exp. Pathol. Pharmakol.
1935, 177, 212.
[3] a) W. Hoppe, F. Brandl, I. Strell, M. Röhrl, I. Gassman, E. Hecker, H.
Bartsch, G. Kreibich, C. V. Szczepanski, Angew. Chem. 1967, 79, 824;
Angew. Chem. Int. Ed. Engl. 1967, 6, 809; b) E. Hecker, H. Bartsch, H.
Bresch, M. G. Schmendt, E. Härle, G. Kreibach, H. Kubinyi, H. U.
Shairer, C. V. Szczepanski, H. W. Thielman, Tetrahedron Lett. 1967,
3165.
[4] E. Hecker, R. Schmidt, Fortschr. Chem. Org. Naturst. 1974, 377.
[5] J. G. Kidd, P. Rous, J. Exp. Med. 1938, 68, 529.
[6] M. Castagna, Y. Takai, K. Kaibuchi, S. Komihiko, U. Kikkawa, Y.
Nishizuka, J. Biol. Chem. 1982, 257, 7847.
[7] L. M. Harwood, A. C. Brickwood, V. Morrison, J. Robertson,
S. Swallow, J. Heterocycl. Chem. 1999, 36, 1391, and references
therein.
[8] a) L. M. Harwood, G. Jones, J. Pickard, R. M. Thomas, D. Watkin, J.
Chem. Soc. Chem. Commun. 1990, 605; b) L. M. Harwood, B. Jackson,
G. Jones, K. Prout, R. M. Thomas, F. J. Witt, J. Chem. Soc. Chem.
Commun. 1990, 608; c) L. M. Harwood, T. Ishikawa, H. Phillips, D.
Watkin, J. Chem. Soc. Chem. Commun. 1991, 527.
Polycyclic natural products that contain an embedded
polyhydroazulene subunit, for example, dilatriol[1a] (1a),
rameswaralide[1b] (1b), grayanotoxin[1c] (1c), and phorbol[1d]
(1d), possess a diversity of biological activities. As such, they
CO2CH3
HO
HO
H
O
H
OH
HO
H
CH3
OH
H
O
1a
1b
OH
OH
H
[9] A. C. Brickwood, M. G. B. Drew, L. M. Harwood, T. Ishikawa, P.
Marais, V. Morisson, J. Chem. Soc. Perkin Trans. 1 1999, 913.
[10] W. Adam, Y.-Y. Chan, D. Cremer, J. Gauss, D. Scheutzow, M. Scindler,
J. Org. Chem. 1987, 52, 2800.
OH
H
H
HO
HO
OH
OH
OH
HO
O
[11] P. A. Krapcho, Synthesis 1982, 893.
OH
OH
[12] L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1984, 25, 5953.
[13] P. Amice, L. Blanco, J. M. Conia, Synthesis 1976, 196.
[14] A. Speicher, T. Eicher, Synthesis 1995, 998.
1d
1c
[15] Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-152923. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
represent interesting yet demanding synthetic challenges and
stimulate the development of new methodologies. The ability
to increase molecular complexity rapidly by cycloaddition
reactions should prove to be particularly interesting in
offering short, atom-economical routes to such targets.
Among these reactions, Rh-[2] and Ru-catalyzed[3] [5‡2]
cycloaddition reactions that involve cyclopropyl enynes have
been discovered by the Wender group and by our group,
respectively. We have shown that the RuII catalyst 2 can
catalyze this process under very mild conditions[3] (room
temperature in acetone within a few hours). This fact
encouraged us to examine the applicability of this strategy
to complex targets represented by 1a ± d, which raises a
number of reactivity and selectivity issues that are addressed
herein.
[16] P. Fischer, G. Schaefer, Angew. Chem. 1981, 93, 895; Angew. Chem.
Int. Ed. Engl. 1981, 20, 863.
[17] This reaction failed to proceed when it was attempted using Et2O as a
solvent, and only starting material was recovered.
[18] a) Zn-mediated: J. H.-H. Chan, B. Rickborn, J. Am. Chem. Soc. 1968,
90, 6406; F. Mohamadi, W. C. Still, Tetrahedron Lett. 1986, 27, 893, and
references therein; b) Sm-mediated: G. A. Molander, L. S. Harring, J.
Org. Chem. 1989, 54, 3525; M. Lautens, P. H. M. Delanghe, J. Org.
Chem. 1992, 57, 798; c) Al-mediated: K. Maruoka, Y. Fukutani, H.
Yamamoto, J. Org. Chem. 1985, 50, 4412; d) Mg-mediated: C. Bolm,
D. Pupowicz, Tetrahedron Lett. 1997, 38, 7349.
The sensitivity of the Ru-catalyzed reactions to steric
hindrance immediately led us to test the ability of 1,2,3-
trisubstituted cyclopropanes to participate in these reactions.
[*] Prof. B. M. Trost, H. C. Shen
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (‡1)650-725-0002
E-mail: bmtrost@leland.stanford.edu
[**] We thank the National Science Foundation and the National Institutes
of Health, General Medical Sciences, for their generous support of our
programs. H.S. is a Stanford Graduate Fellow. Mass spectra were
provided by the Mass Spectrometry Facility of the University of
California, San Francisco, which is supported by the NIH Division of
Research Resources.
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