Dynamic kinetic resolution during a vinylogous Payne rearrangement: A concise synthesis of the polar pharmacophoric subunit of (+)-scyphostatin

Article abstract of DOI:10.1021/ol902459z

"Chemical Equation Presented" The diastereomeric epoxycyclohexenols 3a/b (obtained via a Wharton rearrangement of a bis-epoxycyclohexanone precursor) were shown to undergo interconversion via a facile vinylogous Payne rearrangement. Mechanistic issues were probed; the doubly O-deuterated analogues underwent this equilibration more slowly than the parent dihydroxy compounds. It was possible to kinetically resolve the mixture of 3a/b under equilibrating conditions by use of Amano PS. This DKR is additionally noteworthy because it sets four stereocenters in a single event.

Full text of DOI:10.1021/ol902459z

ORGANIC
LETTERS
2010
Vol. 12, No. 1
52-55
Dynamic Kinetic Resolution During a
Vinylogous Payne Rearrangement: A
Concise Synthesis of the Polar
Pharmacophoric Subunit of
(+)-Scyphostatin
Thomas R. Hoye,* Christopher S. Jeffrey, and Dorian P. Nelson
Department of Chemistry, 207 Pleasant Street, SE, UniVersity of Minnesota,
Minneapolis, Minnesota 55455
hoye@umn.edu
Received October 26, 2009
ABSTRACT
The diastereomeric epoxycyclohexenols 3a/b (obtained via a Wharton rearrangement of a bis-epoxycyclohexanone precursor) were shown to
undergo interconversion via a facile vinylogous Payne rearrangement. Mechanistic issues were probed; the doubly O-deuterated analogues
underwent this equilibration more slowly than the parent dihydroxy compounds. It was possible to kinetically resolve the mixture of 3a/b
under equilibrating conditions by use of Amano PS. This DKR is additionally noteworthy because it sets four stereocenters in a single event.
Scyphostatin (1) is regarded as the most specific and potent
inhibitor (IC50 ) 1.0 µM) of neutral sphingomyelinase, an
encouraging pharmacological target for treating inflammation
and immunological and neurological disorders.1 As can be
seen from its structure (Figure 1), scyphostatin (1) features
two principal moieties: a densely functionalized epoxycy-
clohexenone polar core and an unsaturated fatty acid side
(1) Claus, R. A.; Dorer, M. J.; Bunck, A. C.; Deigner, H. P. Curr. Med.
Chem. 2009, 16, 1978–2000.
Figure 1. Structure of (+)-scyphostatin (1).
(2) Wascholowski, V.; Giannis, A.; Pitsinos, E. N. Chem. Med. Chem.
2006, 1, 718–721.
(3) (a) Inoue, M.; Yokota, W.; Murugesh, M. G.; Izuhara, T.; Katoh, T.
Angew. Chem., Int. Ed. 2004, 116, 4303–4305. (b) Inoue, M.; Yokota, W.;
Katoh, T. Synthesis 2007, 622–637. (c) Takagi, R.; Miyanaga, W.; Tojo,
K.; Tsuyumine, S.; Ohkata, K. J. Org. Chem. 2007, 72, 4117–4125. (d)
Fujioka, H.; Sawama, Y.; Kotoku, N.; Ohnaka, T.; Okitsu, T.; Murata, N.;
Kubo, O.; Li, R.; Kita, Y. Chem.sEur. J. 2007, 13, 10225–10238, and
references therein to the many studies of fragment synthesis.
chain. The biological activity of scyphostatin is believed to
be associated with its epoxyenone headgroup.2 That fact,
coupled with the unusual structure of this pharmacophore,
has motivated many synthetic efforts.3
10.1021/ol902459z  2010 American Chemical Society
Published on Web 12/07/2009

Scheme 1
.
Plan for Synthesis of the Polar Subunit of
Scheme 2. Synthesis of Allylic Alcohols 3
(+)-Scyphostatin (1)
The synthesis commenced with oxidative dearomatization
of the phenol 5 using phenyliodine diacetate (PIDA) to
provide the dienone 6 in 52% yield (Scheme 2). Alterna-
tively, singlet oxygen oxidation of 5 under basic conditions
followed by reduction with DMS also gave the dienone 6 in
a similar yield (45%).8
Here we report a dynamic kinetic resolution (DKR) that
is coupled to a reversible (and rare4) vinylogous Payne
rearrangement (cf. graphical abstract above). The DKR was
achieved using a lipase (Amano PS) as the chiral discrimina-
tor to generate a product, 9a, that contains many of the
constitutional and configurational features of (+)-scyphos-
tatin (1).5
Epoxidation of the dienone 6 with H2O2/NaOH produced
the diepoxide 4 as a single diastereomer,7 and treatment with
hydrazine to effect Wharton rearrangement gave a nearly
1:1 ratio of the allylic alcohols 3a and 3b (30-40% over
two steps). It is noteworthy that sequential application of a
1
Our analysis (Scheme 1) of the scyphostatin core revealed
that it might be formed from a protected amino alcohol such
as the Troc-acetonide 2 (Troc ) Cl3CCH2OCO). We hoped
to make the epoxycyclohexenone 2 via an oxidative DKR
of the pseudoenantiomers 3a and 3b, under conditions where
the stereoisomers would equilibrate via a vinylogous Payne
rearrangement (see curly arrows, Scheme 1). If successful,
such a DKR would be significant because it would establish
three stereocenters in one step. The mixture of allylic alcohols
3 could arise from the Wharton rearrangement of the
diepoxide 4, another example of a rarely seen transforma-
tion.6 We envisioned that the syn-diepoxide 4 could be made
by oxidative dearomatization of the L-tyrosine derivative 5
followed by bis-epoxidation cis to the tertiary hydroxyl
group.7
set of such elementary reagents as O2, H2O2/NaOH, and
NH2NH2 affords a product having the molecular complexity
of 3a/b from a simple phenolic precursor.
The allylic alcohol diastereomers 3a and 3b were separated
by HPLC (SiO2). The equilibration of each of these isolated
diastereomers back to a mixture of 3a and 3b would
implicate a vinylogous Payne rearrangement. This equilibra-
tion occurred slowly upon heating (80 °C) in deuterated
solvents [CDCl3 and d6-acetone (Scheme 3, top)]. A ca. 1:1
ratio of 3a and 3b was reestablished after heating for 3 days
(half-life ca. 1 day).
Because this equilibration occurred under such mild (and
essentially neutral) conditions, we wondered if the tertiary
alcohol could be acting as an intramolecular H-bond donor
to the epoxide in 3,9 thus lowering the activation barrier of
this vinylogous Payne rearrangement. Intramolecular proton-
shuttling through a locally symmetrical transition state
geometry like 7 (Scheme 3, bottom) was an attractive
conceptualization of the process.10 This mechanistic thinking
was probed by comparing the rate of rearrangement of 3a
versus its deuterated analogue. Thus, parallel experiments
(4) The only example we know of this type of rearrangement (i to ii)
occurs under silylative conditions: Myers, A. G.; Siegel, D. R.; Buzard,
D. J.; Charest, M. G. Org. Lett. 2001, 3, 2923–2926.
(5) (a) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita,
T. J. Am. Chem. Soc. 1997, 119, 7871–7872. (b) Nara, F.; Tanaka, M.;
Hosoya, T.; Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 525–530.
(c) Nara, F.; Tanaka, M.; Masuda-Inoue, S.; Yamasato, Y.; Doi-Yoshioka,
H.; Suzuki-Konagai, K.; Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531–
535.
(8) Saito, I.; Chujo, Y.; Shimazu, H.; Yamane, M.; Matsuura, T.;
Cahnmann, H. J. J. Am. Chem. Soc. 1975, 97, 5272–5277.
(9) That the degree of hydrogen bonding is substantial in each of 3a
and 3b is supported by the NMR observation of coupling of both of their
hydroxyl protons to, for the secondary hydroxyl, the vicinal/allylic proton
at C3R/S (3J ) ∼12 Hz) and, for the tertiary hydroxyl, long range coupling
(4J ) ∼1.5 Hz) to a methylene proton in the sidechain.
(6) Wharton on a diepoxyketone: (a) Ichihara, A.; Oda, K.; Kobayashi,
M.; Sakamura, S. Tetrahedron 1980, 36, 183–188. (b) Aoyagi, Y.;
Hitotsuyanagi, Y.; Hasuda, T.; Fukaya, H.; Takeya, K.; Aiyama, R.;
Matsuzaki, T.; Hashimoto, S. Biorg. Med. Chem. Lett. 2006, 16, 1947–
1949.
(10) For other examples of internal hydrogen-bond catalysis, see: (a)
Choy, W.; Reed, L. A., III; Masamune, S. J. Org. Chem. 1983, 48, 1137–
1139. (b) Cox, C. D.; Siu, T.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2003, 42, 5625–5629. (c) Stark, L. M.; Pekari, K.; Sorensen, E. J. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 12064–12066.
(7) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Chem.
Commun. 1992, 1589–1591.
Org. Lett., Vol. 12, No. 1, 2010
53

Sigman,11b or Xia11c proved effective. We successfully used
the Noyori conditions to oxidize the simple allylic alcohol
(()-8a to enone 8b [5 mol % p-cymene·RuTsDPEN;
progress slowed substantially at ca. 50% conversion (1H
NMR analysis)]. When we repeated this experiment, now
with a mixture of substrates (()-8a and 3a/b, we observed
that (()-8a did not turn over. This suggested that vicinal
diol 3 (or initially oxidized products derived therefrom) might
be inhibiting this catalytic system.
Scheme 3. Vinylogous Payne Rearrangement of 3a/b
Scheme 5. Lipase-Mediated DKR
were performed in which diastereomerically pure 3a was
heated in acetone containing ca. 7 vol% H2O versus D2O;
reaction progress of each was monitored by 1H NMR
spectroscopy. Indeed, the D2O sample equilibrated at roughly
half the rate of the H2O sample, supporting the view that
O-H bond cleavage is involved in the rate-limiting event.
Also, the rate of equilibration of the H2O-spiked acetone
reaction mixture was very similar to that when no H2O was
added, suggesting that this change in medium did not
appreciably alter the operative mechanism.
Scheme 4. Attempted Oxidative DKR
We then turned attention to a lipase-mediated DKR
(Scheme 5).12 Exposure of the mixture of 3a/b to Amano
PS in hexanes containing 5 equiv of vinyl acetate at ambient
temperature resulted in slow but steady conversion. A single,
diasteromerically pure acetate was produced [46% yield
following a 14-day reaction time and HPLC purification
(SiO2)]. This acetate was assigned structure 9a on the
following basis. The more polar alcohol, which turned out
to have the configurations depicted in 3b, was converted to
its R- and S-Mosher ester R-10b and S-10b (via treatment
with S- and R-MTPA-Cl, respectively). Analysis13 showed
that the configuration of the carbinol center in 3b was S,
thereby establishing our structure assignment for both 3a and
3b.
With the viability of the vinylogous Payne rearrangement
established, we proceeded to study a DKR that would
selectively drain one of 3a or 3b from the equilibrating
mixture. We first examined an oxidative resolution strategy,
which would have provided the epoxycyclohexenone core
of scyphostatin (cf. 2, Scheme 4) directly. Unfortunately,
none of the asymmetric oxidative methods of Noyori,11a
Each of 3a and 3b was then independently converted to
its acetate ester 9a and 9b, respectively (Scheme 5). The
former was identical to the acetate generated by lipase-
catalyzed acetylation (see above), an outcome that, inciden-
tally, is consistent with the model of Kazlauskas for the
(12) Ghanem, A.; Aboul-Enein, H. Y. Tetrahedron: Asymmetry 2004,
15, 3331–3351.
(11) (a) Hashiguchi, S.; Fujii, S.; Haack, K.-J.; Matsumura, K.; Ikariya,
T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288–290. (b) Jensen, D. R.;
Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475–7476.
(c) Sun, W.; Wang, H.; Xia, C.; Li, J.; Zhao, P. Angew. Chem., Int. Ed.
2003, 42, 1042–1044.
(13) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451–
2458.
(14) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656–2665.
54
Org. Lett., Vol. 12, No. 1, 2010

kinetic selectivity of lipases.14 To establish that a DKR was
operative, the lipase experiment was repeated starting with
pure 3b as the substrate. After 14 days (and at ca. 50%
conversion), a ca. 2:1:1 ratio of 9a:3a:3b had been estab-
lished, unambiguously demonstrating that the vinylogous
Payne rearrangement-based DKR was indeed taking place.
In conclusion, a new strategy for synthesis of the epoxy-
cyclohexenone core of (+)-scyphostatin (1) has been estab-
lished. It allows concise and stereoselective access to
molecules containing the pharmacophoric core of 1 that could
be of biological interest. An example of the rare, vinylogous
Payne rearrangement, which likely proceeds via a unimo-
lecular (and an unusual type of) prototropic shift, has been
uncovered. Furthermore, this transformation was shown to
be a viable basis for a DKR. Finally, this DKR is additionally
noteworthy because it sets four stereocenters in a single event
(cf. 3a + 3b to 9a, Scheme 5).
Scheme 6. Oxidation to Epoxycyclohexenones 2 and 11
Acknowledgment. These studies were supported by the
National Institute of General Medical Sciences (GM-65597)
and the National Cancer Institute (CA-76497) of the United
States National Institutes of Health.
Each pure allylic alcohol 3a and 3b was oxidized under
Swern conditions to furnish both the epoxycyclohexenone
2 found in (+)-scyphostatin and its tris-epimer 11 (Scheme
6). Selective removal of the Troc group proved to be
problematic; but this was not surprising given the known
sensitivity of the epoxy-alkenols, -alkenyl acetates, and
-enones of this family.3
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902459Z
Org. Lett., Vol. 12, No. 1, 2010
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