Use of the vicinal element effect for regiochemical control of quinone substitutions and its implication for convergent mitomycin construction.

Article abstract of DOI:10.1021/ol016625z

[reaction--see text] Nucleophilic substitution reactions of 2-methoxy-3-alkyl-p-benzoquinones are described as they relate to the construction of the mitomycin backbone. Normally controlled by activating groups attached to the olefin, the observed regioselection in these cases is determined by the deactivating substituent. Approximation of carbonyl activating ability would not have predicted the behavior of two systems investigated in which the poorer of two leaving groups is substituted in each case.

Full text of DOI:10.1021/ol016625z

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3695-3697
Use of the Vicinal Element Effect for
Regiochemical Control of Quinone
Substitutions and Its Implication for
Convergent Mitomycin Construction
Amie L. Cox and Jeffrey N. Johnston*
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405-7102
jnjohnst@indiana.edu
Received August 21, 2001
ABSTRACT
Nucleophilic substitution reactions of 2-methoxy-3-alkyl-p-benzoquinones are described as they relate to the construction of the mitomycin
backbone. Normally controlled by activating groups attached to the olefin, the observed regioselection in these cases is determined by the
deactivating substituent. Approximation of carbonyl activating ability would not have predicted the behavior of two systems investigated in
which the poorer of two leaving groups is substituted in each case.
The chemistry of the quinone has been studied for over a
century and continues to demand attention by virtue of its
presence in antitumor quinone natural products such as (-)-
saframycin A1 and nat-mitomycin C2,3 (Figure 1). Most
quinone transformations fall within the classifications of
redox, cycloaddition, and substitution reactions, and attendant
reactivity is generally predictable by approximation of the
electronics of each enone π-system.4
Our interest in the mitomcyins led us to reinvestigate the
disconnections C9-C8a/N4-C4a studied extensively by
Rapoport.5 The straightforward nature of this strategy
notwithstanding, attempts by Rapoport to effect direct C9-
C8a coupling between dibromoquinone 1 and vinylogous
amide 2 resulted only in the opposite (C9-C4a) regiochemi-
cal outcome (3a).6 In this Letter, we describe the develop-
ment of a straightforward solution to this problem that
emphasizes the fact that the addition step of nucleophilic
additions to activated olefins is rate-limiting.7
Our studies have focused on the behavior of pyrrolidinyl
enamine 4. Although substantially more reactive than 2,
enamine 4 behaved similarly by producing the undesired
regioisomer 5 in the coupling process (Scheme 1). This
behavior follows from examination of the intermediate
(1) Leading reference: Myers, A. G.; Plowright, A. T. J. Am. Chem.
Soc. 2001, 123, 5114-5115, and ref 9 therein.
(2) Total synthesis of rac-mitomycin C: (a) Kishi, Y. J. Nat. Prod. 1979,
42, 549-568. (b) Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1989, 111,
8303-8304.
(3) Recent synthetic studies: (a) Coleman, R. S.; Chen, W. Org. Lett.
2001, 2, 1141-1144. (b) Papaionnou, N.; Evans, C. A.; Blank, J. T.; Miller,
S. J. Org. Lett. 2001, 3, 2879-2882.
(4) Finley, K. T. In Supplement E: The Chemistry of Hydroxyl, Ether,
and Peroxide Groups; Patai, S., Ed.; Wiley: New York, 1993; Vol. 2,
Chapter 19.
(5) Shaw, K. J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515-
4523.
Figure 1. Representative quinone-derived alkaloids.
10.1021/ol016625z CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/23/2001

Scheme 1. Regioselective Quinone-Enamine Couplings
Table 1. Regioselective Substitutions of 1 with Methoxide (eq
2)a
a See Supporting Information for full experimental details. b Measured
1
using H NMR (400 MHz). c Isolated yield.
and magnesium counterions, the latter provided significantly
shorter reaction times (2 h vs 3 d). During an optimization
process that included both acidic (Lewis and protic acids)
and basic conditions (including the use of counterion-
sequestering reagents), it was found that additions using polar
aprotic solvents reversed the regioselection in favor of 7.
Again, a maximum of 2:1 selectivity could be achieved by
use of potassium methoxide (Table 1, entry 5).
A possible explanation for the divergent behavior of these
substitutions follows from rate-limiting methoxide addition.
Product ratios might simply reflect a solvent-induced reversal
of the addition rates to form 8 and 9 (Scheme 2). A 1,2-
adducts whose relative energies might be reflected by the
difference in pKa between tert-butyl acetate (30.3) and
acetone (26.5) in DMSO.8 The possibility that Lewis acid
might reverse the sense of regioselection according to the
Engler protocol9 was investigated but found to be uniformly
unsuccessful. This was not entirely unexpected since coupling
of 1 with 4 at -78 °C is instantaneous and indicated by an
immediate color change from orange (1) to deep blue (5).
Hence, the substitutionally labile olefin of dibromoquinone
10
1 conforms to the Vicinal element effect (eq 1).
Scheme 2. Solvent-Induced Reversal of Regioselection
It was therefore reasonable to assume that substitution first
with methoxy might be both (1) highly regioselective in
direction and magnitude by analogy to substitutions with 2
and 4 and (2) a means to electronically differentiate the two
olefinic sites of substitution such that C9-C8a coupling can
be effected. This was not the case.
Treatment of 1 with buffered methanol was significantly
less regioselective than enamine addition, providing a 1.5:1
ratio of bromoquinones 6 and 7 (Table 1, entry 3).11,12
Selectivity could be increased only marginally by addition
of preformed sodium methoxide (Table 1, entry 2). Although
the same level of regioselection was observed using sodium
carbonyl addition/1,2-migration to the enone cannot be
discounted, but we observe no product formation using protic
acid conditions that might favor this process.4,13
To model couplings relevant to mitomycin construction,
quinones 6 and 7 were independently exposed to enamine 4
(Scheme 3). The blue quinones formed rapidly at 0 °C, and
(6) Recourse was eventually made to N4-C4a bond formation prior to
C9-C8a, but this sequence has not yet enabled the total synthesis. (a) Luly,
J. R.; Rapoport, H. J. Org. Chem. 1984, 49, 1671-1672. (b) Luly, J. R.;
Rapoport, H. J. Am. Chem. Soc. 1983, 105, 2859-2866. (c) Luly, J. R.;
Rapoport, H. J. Org. Chem. 1981, 46, 2745-2752.
1
inspection of the H NMR of the crude reaction mixture
(7) Modena, G. Acc. Chem. Res. 1971, 4, 73.
suggested the presence of only one coupling product of 4 in
each case. The thermally labile adducts could be retrieved
in pure form after chromatography over neutral alumina
(jacketed column, ice-water cooling), and structural assign-
ments were possible by HMBC. Additionally, the same
product was formed upon coupling of 4 with either 1 or 6.
The isolated yields reflect the sensitivity of these adducts to
(8) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463. (b) Bordwell,
F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327-4331.
(9) (a) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444-2457.
(b) Engler, T. A.; Iyengar, R. J. Org. Chem. 1998, 63, 1929-1934.
(10) (a) Bunnett, J. F.; Garbisch, E. W. Jr.; Pruitt, K. M. J. Am. Chem.
Soc. 1957,79, 385. (b) Bunnett, J. F. Q. ReV. (London) 1958, 12, 1.
(11) Huisman, H. O. Recueil 1950, 69, 1133-1156.
(12) Structural assignments were made by HMBC and NOE measure-
ments in both cases. See Supporting Information for details.
3696
Org. Lett., Vol. 3, No. 23, 2001

Scheme 3. Enamine-Methoxybromoquinone Couplings
Table 2. LUMO Coefficients and Charge for Each Carbon of
Quinones 1, 6, and 7 Determined by Semiempirical (PM3)
Calculationsa
1
chromatography since 400 MHz H NMR analysis of the
unpurified reaction mixtures revealed clean conversion. A
competition experiment involving equimolar amounts of 4,
6, and 7 confirmed the expectation that substitution of the
vinylogous ester is more rapid (>95:5 5:10) than substitution
of the vinylogous carbonate.
The results of the competition experiment are not consis-
tent with a 1,2-addition/1,2-migration pathway, so only
conjugate addition/â-elimination pathways are considered.14
The observation that the poorer leaving group is preferentially
substituted is consistent with a mechanism in which enamine
addition to the enone π-bond is rate-determining.15 That the
methoxy would be substituted preferentially in the case of
7, however, is nonobvious since Vicinal element effects
predict control by the stronger actiVating group, which in
this case is the carbonyl at C1 (Table 2 numbering).16
We turned to semiempirical calculations (Table 2) to
determine whether this behavior might be predictable, using
the assumption that ground-state polarization of the accepting
olefin might be extrapolated to the relative energies of the
nucleophile-quinone Michael adducts.17 The nearly identical
charges at carbonyl C1 (vinylogous enone) and carbonyl C4
(enone) indicate that oxygen n-donation to the carbonyl
π-bond is not detected in these calculations. However,
oxygen n-donation to the C2-C3 π-bond is revealed by
significant negative charge at C3. Hence, the calculations
appear to identify only local electronic perturbations.
For enamine additions to 1, the high degree of regiose-
lectivity derives from, and is consistent with, the electronic
nature of enones C5/C1 and C6/C4 as determined by a
deactivating resonance contribution by the C2-methoxy into
C4. The unique characteristic of enamine additions to 6 and
7 is that an overriding Vicinal element effect by the bromine
substituent is expressed. The methoxy carbon is more positive
and carries a larger LUMO coefficient relative to the
bromine-substituted carbon in both quinones. An alternative
a Using PCModel (Serena Software) and the MOPAC suite. AM1
calculations revealed identical trends. Numbers in bold correspond to
experimentally observed sites of nucleophilic substitution. b Raw coefficients
must be squared for comparison.
view is that addition to the bromine-substituted carbon is
strongly disfavored by a donating resonance effect by the
methoxy group. That the methoxy substituent exerts a
deactivating effect is supported by slower reaction of enamine
4 with 6 and 7 relative to 1.
In closing, several unsymmetrical benzoquinone systems
have been described that undergo substitution with moderate
(2:1) to high (>95:5) regioselectivity. The present level offers
an improvement in coupling selectivity toward construction
of the mitomycin backbone but also identifies a new target
(7) for coupling that might be prepared via a more direct
route.
Additionally, interest in the development of nonlinear
optics (NLO) based on quinonic systems18 might now
consider â-halo vinyl ether systems as alternatives to
traditional 1,2-dihaloethylenic acceptors, since the former are
more regioselective and utilize less halogenated substrates.
Acknowledgment. We are thankful to Prof. Joseph
Gajewski (IU) for advice regarding the calculations. A.L.C.
is grateful for Paget (1999-2000) and GAANN (2000-
2001) fellowship support. Acknowledgment is made to the
donors of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research.
(13) (a) Evans, D. A.; Hoffman, J. M. J. Am. Chem. Soc. 1976, 98, 1983-
1984. (b) Evans, D. A.; Hoffman, J. M.; Truesdale, L. K. J. Am. Chem.
Soc. 1973, 95, 5822-5823.
(14) Experiments suggest that these product ratios are kinetic distribu-
tions.
(15) Rappoport, Z. In AdVances in Physical Organic Chemistry; Gold,
V., Ed.; Academic: London, 1969; Vol. 7, Chapter 1.
(16) For examples of the vicinal element effect (methoxy-substitution)
in quinones where enone electronics are not overridden, see: (a) Tatsuta,
K.; Mukai, H.; Mitsumoto, K. J. Antibiot. 2001, 54, 105-108. (b) Reference
11.
Supporting Information Available: General experimen-
tal procedures and spectral data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016625Z
(17) Rozeboom, M. D.; Tegmo-Larsson, I.-M.; Houk, K. N. J. Org.
Chem. 1981, 46, 2338-2345
(18) Alnabari, M.; Bittner, S. Synthesis 2000, 1087-1090.
Org. Lett., Vol. 3, No. 23, 2001
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