Stereoselective conjugate addition directed by an enantiomerically pure ketal. Preparation of the cyclohexanone fragment of N-methylwelwitindolinone C isothiocyanate

Article abstract of DOI:10.1055/s-1998-1886

A cyclohexanone intermediate to be employed in the synthesis of the marine natural product N-methylwelwitindolinone C isothiocyanate has been prepared. The synthesis is diastereoselective for the production of the C12 quaternary center, which is obtained via a conjugate addition reaction directed by an adjacent chiral, nonracemic ketal. A single crystal X-ray analysis of a derivative of the final product established the absolute stereochemistry at C12.

Full text of DOI:10.1055/s-1998-1886

October 1998
SYNLETT
1105
Stereoselective Conjugate Addition Directed by an Enantiomerically Pure Ketal. Preparation
of the Cyclohexanone Fragment of N-Methylwelwitindolinone C Isothiocyanate.
,1a
1a
1a,2a
1a,2b
1b,3
Joseph P. Konopelski,* Hongbo Deng, Kai Schiemann,
Joseph M. Keane,
and Marilyn M. Olmstead
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, and Department of Chemistry, University of California,
Davis, CA 95616
Phone: 408-459-2935, FAX: 408-459-2935, E-mail: joek@chemistry.ucsc.edu.
Received 19 August 1998
Abstract: A cyclohexanone intermediate to be employed in the
synthesis of the marine natural product N-methylwelwitindolinone C
isothiocyanate has been prepared. The synthesis is diastereoselective for
the production of the C12 quaternary center, which is obtained via a
conjugate addition reaction directed by an adjacent chiral, nonracemic
ketal. A single crystal X-ray analysis of a derivative of the final product
established the absolute stereochemistry at C12.
were not sufficiently high to warrant continued study. Our present
synthetic route to 2 is outlined in Scheme 1, and begins with 1,4-
cyclohexanediol. After selective monooxidation with Jones reagent, the
resulting keto-alcohol is protected as the corresponding ketal by reaction
with (R,R)-hydrobenzoin (70% overall). Use of the (R,R)-isomer of
hydrobenzoin to form an enantiomerically pure ketal at the C13 center
serves the dual purpose of directing the formation of the correct absolute
stereochemistry at the adjacent C12 center and of maintaining C13 in
the ketone oxidation state for transformation, in the final synthetic
One persistent problem in cancer chemotherapy is that of multiple drug
resistance (MDR), in which the disease cells develop resistance not only
to the initial chemotherapeutic agent but also to any number of other
clinically useful drugs. This MDR problem is very difficult and not well
defined. Recent experiments have indicated that certain indole alkaloids
sequences, to the desired vinyl chloride functionality. Oxidation
12
utilizing the TEMPO/bleach protocol
(96%) affords ketone 3.
Chromium-based oxidation agents were less effective in this step.
13
Incorporation of the carbomethoxy group follows standard protocols
and yields 4 in 95% yield.
4
are among the most active agents in reversing MDR. These include
The route from 4 to 2 requires two successive oxidation/conjugate
5
natural products such as reserpine and certain derivatives as well as
13
addition sequences. Following the report of Delongchamps,
a
6
synthetic indoles. Preliminary work on a pharmacophore model for
selenation-deselenation protocol is employed to introduce a double
bond into the six-membered ring, giving 5 in 84% yield from 3. Double
bond incorporation could also be effected with DDQ but difficulties
were experienced in driving the reaction to completion. After some
experimentation with different copper-based methods, incorporation of
5
MDR reversal activity has also been presented. Newly isolated natural
7
8
products continue to capture the interest of industrial and academic
researchers, as do fully synthetic MDR reversal agents.
9
the C12-methyl group was achieved in excellent yield through the use of
14,15
MeMgBr/ZnCl /TMSCl.
The second oxidation step in the sequence
2
was, not surprisingly, more difficult than the first. After some
experimentation, deprotonation with NaH in the selenation step and
oxidation with m-CPBA to form the selenoxide proved superior to other
reagents and resulted in an overall 61% yield of desired material 6 from
5.
Recently Moore and co-workers isolated and characterized several
10
structurally unusual alkaloids from a variety of blue-green algae. One
of these compounds, N-methylwelwitindolinone C isothiocyanate (1),
was shown to reverse P-glycoprotein-mediated MDR in a vinblastine-
resistant subline of a human ovarian adenocarcinoma. The structure of
1, particularly the seven-membered ring spanning C3 and C4 of the
oxindole system, presents an attractive synthetic target. Herein we
report the synthesis of 2, a key intermediate in our convergent strategy
toward 1.
Scheme 1
a) 1) Jones reagent; 2) (R,R)-hydrobenzoin, PTSA, 70%; b) TEMPO
(cat.), bleach, 96%; c) (MeO) CO, NaH, 95%; d) 1)PhSeBr, C H N, 2)
2
5 5
H O , 84%; e) MeMgBr, ZnCl , TMSCl; f) 1)PhSeBr, NaH, 2) m-
2
2
2
CPBA, 61% from
5
Key to the success of this synthesis is a diastereoselective conjugate
addition reaction to the α-carbomethoxy-β-methyl-α,β-unsaturated
cyclohexenone
quaternary center. We
to set the absolute stereochemistry at the C12
6
16,17
18
and others
had previously studied
hydrobenzoin-based ketals and found them to be excellent directing
groups for reactions at adjacent centers. Since the enantiomeric
11
19
We initially explored the method of Lukes, et al. for preparation of the
hydrobenzoins are available both commercially and synthetically on
20
key starting material for our synthesis. However, yields by this sequence
large scale, this diol is an attractive enantiomerically-pure auxiliary.

1106
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SYNLETT
We envisioned that a suitable vinyl nucleophile would encounter
significant steric strain from the proximal phenyl group of the auxiliary
in an approach to the C12 center from the top (β) face (Figure 1).
Conversely, the approach to the α face is removed from either of the
auxiliary aryl groups and is relatively free from strain. However, the
extreme steric demands placed on this conjugate addition reaction by
the full substitution pattern at the α, β, and γ positions of the substrate
Simple hydrolysis of the methyl ester functionality of 2 led by
decarboxylation to the production of 8 in 78% yield. A single crystal X-
ray analysis of 8, shown below without hydrogens, reveals both the
proximity of the nearest phenyl group to the C12 substituents and the
desired absolute stereochemistry at C12, in complete accord with our
initial analysis.
25
An indole system suitable for the synthesis of 1 is available by
21
were a deep concern, as were the previous studies of Jung and Lew. In
modification of our published work directed at the total synthesis of the
26
this work, which involved cuprates derived from alkyllithium reagents
marine natural product diazonamide A. Studies directed at the
and performed in Et O on cyclopentene ketone systems, only modest (at
completion of the synthesis of 1 are underway and will be reported in
2
best, 2:1) diastereoselectivity was observed.
due course.
Acknowledgments: We are grateful to the Elsa U. Pardee Foundation
and the UC Cancer Research Coordinating Committee for funding this
work. In addition, one of us (JMK) would like to thank the NSF
Undergraduate Research Experience Program (Grant CHE-9619961) for
support. NMR equipment grants from NSF (BIR-94-19409) and the
Elsa U. Pardee Foundation are gratefully acknowledged. Finally, we
would like to thank our colleagues Professor Rebecca Braslau (UCSC)
and Professor Bruce Lipshutz (UCSB) for many helpful discussions
over the course of this work.
References and Notes
Figure 1
(1) a) University of California, Santa Cruz. b) University of
California, Davis.
In the event, the crucial second conjugate addition required extensive
optimization. Substituting vinylmagnesium bromide for the
corresponding methyl Grignard reagent under the conditions employed
in the reaction of 5 was completely ineffective. Reagents prepared from
various copper(I) sources with or without additional reagents (TMSCl,
(2) Present Address: Warner Lambert, Parke-Davis, 2800 Plymouth
Road, Ann Arbor, MI 48105. b) NSF Research Experience for
Undergraduates participant, UCSC, Summer 1997.
(3) Author to whom correspondence concerning X-ray
crystallography should be addressed.
BF •Et O, PBu ) all proved less than satisfactory. Success was finally
3
2
3
achieved through the aegis of vinyl magnesium bromide in the presence
(4) Zamora, J.M.; Pearce, H.L.; Beck, W.T. Mol. Pharmacol. 1988,
33, 454-62.
22
of excess CuCN to introduce the desired absolute configuration at
C12.
(5) Pearce, H.L.; Safa, A.R.; Bach, N.J.; Winter, M.A.; Cirtain, M.C.;
Direct analysis of
proved to be complicated by the keto-enol
2
Beck, W.T. Proc. Natl. Acad. Sci, USA 1989, 86, 5128-32.
tautomerism inherent in the β-ketoester functionality. This problem was
(6) Matsumoto, T.; Fujii, R.; Sugita, M.; Sumizawa, T.; Sakai, S.;
Takahashi, T.; Sueda, N.; Furukawa, T.; Akiyama, S.; Nagata, Y.
Anti-Cancer Drug Design 1994, 9, 251-61.
removed by making C11 a nonstereogenic center. To this end, treatment
of a crude reaction mixture of with diphenyl chlorophosphate and
2
NaH led to the enol phosphate derivative in 85% overall yield for the
7
1
two steps. Analysis by 500 MHz H NMR indicated an 81:19 mixture of
(7) Hochlowski, J.E.; Mullally, M.M.; Spanton, S.G.; Whittern, D.N.;
isomers, a significant improvement over the selectivity seen by the
Hill, P.; McAlpine J. Antibiot. 1993, 46, 380-6.
21,23
UCLA team.
Other Grignard reagents (PhMgBr and EtMgBr in
(8) a) Marsden, S.P.; Depew, K.M.; Danishefsky, S.J. J. Am. Chem.
Soc. 1994, 116, 11143-4; b) Andrus, M.B.; Lepore, S.D.; Turner,
T.M. J. Am. Chem. Soc. 1997, 119, 12159-69; c) Dinh, T.Q.; Du,
X.H.; Smith, C.D.; Armstrong, R.W. J. Org. Chem. 1997, 62,
6773-83.
THF, C H MgCl in Et O) proved less successful. The selectivities
6
11
2
were uniformly modest (1:1 to 2:1) with significant 1,2-addition product
being formed when the larger phenyl and cyclohexyl reagents were
employed. Thus, at least under these conditions and substrate
specifications, there are unique attributes to the vinylmagnesium
bromide/CuCN reagent that are not shared by aromatic or aliphatic
(9) a) Dantzig, A.H.; Shepard, R.L.; Cao, J.; Law, K.L.; Ehlhardt,
W.J.; Baughman, T.M.; Bumol, T.F.; Starling, J.J. Cancer Res.
1996, 56, 4171-9. b) Suzuki, T.; Fukazawa, N.; San-nohe, K.;
Sata, W.; Yano, O.; Tsuruo, T. J. Med. Chem. 1997, 40, 2047-52.
counterparts that result in a synthetically viable approach to the
24
quaternary center in via conjugate addition technology.
2
(10) Stratmann, K.; Moore, R.E.; Bonjouklian, R.; Deeter, J.B.;
Patterson, G.M.L.; Shaffer, S.; Smith, C.D.; Smitka, T.A. J. Am.
Chem. Soc. 1994, 116, 9935-42.
(11) Lukes, R.M.; Poos, G.I.; Sarett, L.H. J. Am. Chem. Soc. 1952, 74,
1401-5.
(12) Anelli, P.L.; Montanari, F.; Quici, S. Org. Synth. 1990, 69, 212-9.
(13) Lavallee, J.-F.; Spino, C.; Ruel, R.; Hogan, K.T.; Deslongchamps,
P. Can. J. Chem. 1992, 70, 1406-26.

October 1998
SYNLETT
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(14) a) Schultz, A.G.; Harrington, R.E. J. Am. Chem. Soc. 1991, 113,
4926-31. b) Posner, G.H.; Hulce, M.; Mallamo, J.P.; Drexler, S.A.;
Clardy, J. J. Org. Chem. 1981, 46, 5244-6.
Solvent effects in copper chemistry are discussed in reference 22.
For a discussion of lithium ion effects, see Seebach, D.; Beck,
A.K.; Studer, A. Modern Synthetic Methods 1995, 7, 1-178.
(15) The diastereoselectivity of this conjugate addition reaction was
approximately 2:1.
(24) The addition of vinyl Grignard reagent/CuCN to 5, in accord with
our other conjugate addition experiments on this compound,
afforded a low yield (38%) of a 2:1 mixture of isomers. Thus, it
appears that the methyl group in 6 exerts a significant influence in
both the yield and stereoselectivity of the conjugate addition
reaction. Figure 1 depicts one of at least two minimum energy
conformations of 6, distinguished by having one or the other of the
C4-O bonds in an axial orientation. At the present time we are not
in the position to determine which of these two conformations is
productive.
(16) Konopelski, J.P.; Boehler, M.A. J. Am. Chem. Soc. 1989, 111,
4515-7.
(17) Eid, Jr, C.N.; Konopelski, J.P. Tetrahedron 1991, 47, 975-92.
(18) For a review, see Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 477-511.
(19) Wang, Z.-M., Sharpless, K.B. J. Org. Chem. 1994, 59, 8302-3.
(20) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995.
(25) The authors have deposited coordinates for structure 8 with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2
1EZ, U.K.
(21) Jung, M.E.; Lew, W. Tetrahedron Lett. 1990, 31, 623-6.
(22) For a full discussion on organocopper chemistry, see Lipshutz,
B.H.; Sengupta, S. Org. React. 1992, 41, 135-631.
(23) A direct comparison between the results of Jung and Lew and our
present results are made difficult due to the differences in solvent
(26) Konopelski, J.P.; Hottenroth, J.M.; Monzó-Oltra; H.; Véliz, E.A.;
(Et O vs. THF) and counterion (Li vs. Mg), which undoubtedly
2
affect the aggregation state of the reactive species in solution.
Yang, Z.-C. Synlett, 1996, 609-11.