Consecutive alkene cross-metathesis/oxonium ylide formation - Rearrangement: Synthesis of the anti-HIV agent hyperolactone C

Article abstract of DOI:10.1021/ol802334y

(Chemical Equation Presented) α-Diazo-β-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed by Rh₂(OAc)₄-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective manner. The methodology has been demonstrated in a concise synthesis of the anti-HIV agent hyperolactone C.

Full text of DOI:10.1021/ol802334y

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5553-5556
Consecutive Alkene Cross-Metathesis/
Oxonium Ylide
Formation-Rearrangement: Synthesis
of the Anti-HIV Agent Hyperolactone C
David M. Hodgson,* Deepshikha Angrish, Stephanie P. Erickson,
Johannes Kloesges, and Caroline H. Lee
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
daVid.hodgson@chem.ox.ac.uk
Received October 13, 2008
ABSTRACT
r-Diazo-ꢀ-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed
by Rh2(OAc)4-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective
manner. The methodology has been demonstrated in a concise synthesis of the anti-HIV agent hyperolactone C.
We previously demonstrated the coupling of two different,
synthetically important transition-metal-catalyzed carbene
Scheme 1. Oxonium Ylide Formation-Rearrangement
transformations (alkene cross-metathesis1 and diazocarbonyl-
derived tandem carbonyl ylide formation-intramolecular 1,3-
dipolar cycloaddition)2 in a one-pot operation to access
complex oxapolycycles.3 This process allowed rapid as-
sembly of complex molecular structures and suggested
further opportunities for combining one-pot alkene cross-
metathesis with other transformations of diazo compounds.
Oxonium ylides (e.g., 2, Scheme 1) are reactive intermedi-
ates with a postively charged oxygen atom bonded to a
carbon possessing an unshared pair of electrons. One
convenient approach to oxonium ylides involves the interac-
tion of a diazocarbonyl-derived metallocarbene with an
unshared pair of electrons from an ethereal oxygen (e.g.,
1f2).2,4 Pirrung5 and Johnson6 independently established
the synthetic utility of tandem oxonium ylide formation-
rearrangement. They explored the intramolecular generation
of diazocarbonyl-derived unsaturated oxonium ylides 2 via
Rh(II) and Cu(II) carbenoids and their subsequent [2,3]
sigmatropic rearrangement to give, for example, dihydro-
furanones 3 (Scheme 1).7
(1) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim,
2003.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons: New York, 1998.
(4) Clark, J. S. Nitrogen, Oxygen and Sulfur Ylide Chemistry; Oxford
University Press: Oxford, 2002; Chapter 1.
(5) Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060–
(3) (a) Hodgson, D. M.; Angrish, D.; Labande, A. H. Chem. Commun.
2006, 627–628. (b) Hodgson, D. M.; Angrish, D. AdV. Synth. Catal. 2006,
348, 2509–2514.
6062.
(6) Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108, 6062–
6063.
10.1021/ol802334y CCC: $40.75
Published on Web 11/17/2008
2008 American Chemical Society

The scope of this chemistry has subsequently been
examined toward the synthesis of several natural products.8
Rapid access to varied 2-substituted dihydrofuranones 3
would be facilitated by late-stage diversification of the
unsaturation in a rearrangement precursor 1 and would also
allow a straightforward analysis of the effect of alkene
substitution on the rearrangement chemistry. Herein, we
describe one-pot alkene cross-metathesis/oxonium ylide
formation and highly diastereoselective [2,3] sigmatropic
rearrangement to access dihydrofuranones and application
of the methodology in a synthesis of hyperolactone C.
First, we examined the viability of allylic ether functional-
ity to undergo cross-metathesis in the presence of a tethered
diazocarbonyl group. Cross-metathesis of R-diazo-ꢀ-ketoester
45,9 with olefins (5-10 equiv) was carried out using Grubbs
II catalyst (5 mol %) in CH2Cl2 at reflux for 14-18 h (Table
1). The substituted alkenes 5 were obtained in moderate to
excellent yields and generally with high stereoselectivity.
Cross-metathesis with 2-methyl-2-butene proceeded smoothly
to give the prenyl ether in excellent yield (entry 1).
Vinylcyclohexane underwent efficient cross-metathesis (89%),
but the sterically hindered 3,3-dimethyl-1-butene gave only
50% cross-metathesis (entries 2 and 3). Styrene and substi-
tuted styrenes were also found to be less efficient partners
during cross-metathesis with allyl ether-tethered R-diazo-ꢀ-
ketoester 4 (entries 4-6), compared to the diazo precursor
to tandem carbonyl ylide formation-1,3-dipolar cycloaddi-
tion;3 however, the reaction proceeded with high stereose-
lectivity to give predominantly E-isomers. R,ꢀ-Unsaturated
esters were quite efficient partners and gave disubstituted
R,ꢀ-unsaturated esters with high stereoselectivity (entries 7
and 8).
Encouraged by the ability of 4 to undergo stereoselective
cross-metathesis in the presence of diazo and allylic ether
functionalities, we examined one-pot cross-metathesis/oxo-
nium ylide formation-rearrangement. The sequence was
carried out using Grubbs II catalyst (5 mol %) with R-diazo-
ꢀ-ketoester 4 and metathesis partner (5-10 equiv) in CH2Cl2
at reflux for 14-20 h, followed by addition of Rh2(OAc)4
(4 mol %) at room temperature (TLC monitoring, ∼12-14
h). The methodology was first tested with 2-methyl-2-butene,
as a closely related prenyl ether had already been shown by
Hashimoto and co-workers to undergo a tandem oxonium
ylide formation/[2,3] sigmatropic rearrangement.10 In the
event, in situ generated prenyl ether 5a gave dihydrofuranone
6a in 87% yield in the one-pot process (compared to 73%
yield obtained with the corresponding methyl ester by
Table 1. Cross-Metathesis and Oxonium Ylide
Formation-Rearrangement Using Diazoester 4
a
Determined by H NMR. b Determined by GC-MS.
1
Hashimoto10 for the ylide transformation only) (Table 1,
entry 1). Vinylcyclohexane also worked efficiently in the one-
pot procedure to give the dihydrofuranone 6b in good yield
(entry 2) and with high diastereoselectivity (90:10). However,
sterically hindered 3,3-dimethyl-1-butene gave the desired
dihydrofuranone 6c in only modest yield (49%), but with
high diastereoselectivity (94:6) (entry 3); no change in dr
was observed when this Rh-catalyzed ylide rearrangement
was carried out at reflux (dr ) 93.5:6.5, with 54% isolated
one-pot yield for 6c), suggesting that the dr of rearrangement
is relatively independent of the reaction temperature. Styrene
and substituted styrenes also gave the dihydrofuranones 6d-f
in moderate yields (51-66%), but with high levels of
diastereoselectivity (entries 4-6). The modest yield during
the one-pot procedure for these olefins likely reflects cross-
metathesis efficiency with R-diazo-ꢀ-ketoester 4 (entries
3-6). The influence of ester functionality on the diastereo-
selectivity of the rearrangement was then studied. Esters
showed excellent diastereoselectivity and very good yields
during the process. No effect of sterics of the ester was
observed. The methyl ester gave >99:1 dr (entry 7), and a
tert-butyl ester gave 98:2 dr (entry 8).
(7) For [2,3] sigmatropic rearrangement of oxonium ylides formed under
Rh2(OAc) catalysis via in situ generated iodonium ylides, see: Murphy,
4
G. K.; West, F. G. Org. Lett. 2006, 8, 4359–4361.
(8) (a) Pirrung, M. P.; Brown, W. L.; Rege, S.; Laughton, P. J. Am.
Chem. Soc. 1991, 113, 8561–8562. (b) Clark, J. S.; Fessard, T. C.; Wilson,
C. Org. Lett. 2004, 6, 1773–1776. (c) Yakura, T.; Muramatsu, W.; Uenishi,
J. Chem. Pharm. Bull. 2005, 53, 989–994. (d) Clark, J. S.; Fessard, T. C.;
Whitlock, G. A. Tetrahedron 2005, 62, 73–78. (e) Clark, J. S.; Hayes, S. T.;
Wilson, C.; Gobbi, L. Angew. Chem., Int. Ed. 2007, 46, 437–440. (f) Clark,
J. S.; Baxter, C. A.; Dossetter, A. G.; Poigny, S.; Castro, J. L.; Wittingham,
W. G. J. Org. Chem. 2008, 73, 1040–1055.
Complete allylic transposition in the above reactions
indicates that from oxonium ylide 2 a pericyclic ([2,3]
sigmatropic rearrangement) pathway is likely preferred over
one involving C-O cleavage-recombination.2,4 In most
cases, diastereoselectivity arising from the ylide rearrange-
(9) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy,
E.; Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983–5986
.
(10) Kitagaki, S.; Yanamoto, Y.; Tsutsui, H.; Anada, M.; Nakajima, M.;
Hashimoto, S. Tetrahedron Lett. 2001, 42, 6361–6364.
5554
Org. Lett., Vol. 10, No. 24, 2008

ment matched the stereoselectivity seen during cross-
metathesis, suggesting one transition-state orientation is
strongly favored (see below). However, a slight erosion of
diastereoselectivity was observed for the olefins bearing tert-
butyl and p-chlorophenyl groups (entries 3 and 6). The
relative stereochemistry of the major diastereomer of 6f was
supported by X-ray crystallographic analysis (Figure 1),11
and the rest of the major dihydrofuranone products 6 were
assigned by analogy.
activity of biyouyanagin A has recently been reported to
reside in the hyperolactone C structural domain.12e The
structural complexity of hyperolactone C and potential as a
new lead in anti-HIV research combine to make it an
attractive target, which we considered could be accessed by
an extension of the above metathesis-oxonium ylide chem-
istry (Scheme 3). Specifically, we envisaged hyperolactone
C as arising from spirolactonization and dehydrogenation of
dihydrofuranone 9. Dihydrofuranone 9 was anticipated to
originate from E-selective cross-metathesis of unsaturated
R-diazo-ꢀ-ketoester 10 and an appropriate partner alkene 11,
followed by oxonium ylide generation and endo-selective
[2,3] sigmatropic rearrangement on the face of the ylide away
from the phenyl group.
Scheme 3. Strategy to Hyperolactone C
Figure 1.
X-ray structure of dihydrofuranone 6f-syn.11
[2,3] Sigmatropic rearrangement of the putative oxonium
ylide intermediates in the above chemistry can in principle
proceed via exo and/or endo transition states (TSs) (Scheme
2). If rearrangement proceeds through an endo-TS, 6-syn
will be obtained; however, if the rearrangement proceeds
through an exo-TS, diastereomer 6-anti will be formed. The
crystal structure for 6f suggests that the ylide rearrangement
proceeds preferentially via an endo-TS. Although the origin
of this stereoselectivity is not currently known, our observa-
tions are in accordance with results obtained by Clark and
co-workers concerning oxonium ylide rearrangement of
R-diazoketones.8b
Oxonium ylide precursor 10 was synthesized by a Lewis
acid catalyzed Mukaiyama-type aldol condensation between
(bis(allyloxy)methyl)benzene13 and the silyl enol ether of
commercially available ethyl diazoacetoacetate (12), follow-
ing a modified literature procedure (Scheme 4).14
As a model study, the R-diazo-ꢀ-ketoester 10 was sub-
jected to Rh2(OAc)4-catalyzed oxonium ylide formation-
rearrangement. The corresponding dihydrofuranone 13 was
obtained in 99% yield with high diastereoselectivity (91:9,
stereochemistry assigned by NOE studies).11 The cross-
metathesis of allyl ether 10 with gem-disubstituted olefins
11 containing requisite oxygen functionality proved chal-
lenging, with benzoyl- or trityl-protected methallyl alcohol
proceeding with modest E:Z selectivity (63:37 and 83:17,
respectively) and in low yields (22% and 6%, respectively).
However, cross-metathesis with 2-methyl-2-butene proceeded
well to give the corresponding prenyl ether in 81% yield
Scheme 2. Rearrangement Transition States
(11) See the Supporting Information for further details.
(12) For isolation and structure elucidation, see: (a) Aramaki, Y.; Chiba,
K.; Tada, M. Phytochemistry 1995, 38, 1419–1421. For previous syntheses,
see: (b) Ueki, T.; Doe, M.; Tanaka, R.; Morimoto, Y.; Yoshihara, K.;
Kinoshita, T. J. Heterocycl. Chem. 2001, 38, 165–172. (c) Kraus, G. A.;
Wei, J. J. Nat. Prod. 2004, 67, 1039–1040. (d) Nicolaou, K. C.; Sarlah, D.;
Shaw, D. M. Angew. Chem., Int. Ed. 2007, 46, 4708–4711. (e) Nicolaou,
K. C.; Wu, T. R.; Sarlah, D.; Shaw, D. M.; Rowcliffe, E.; Burton, D. R.
J. Am. Chem. Soc. 2008, 130, 11114–11121.
Hyperolactone C (7)12 is a structurally interesting spiro-
lactone with adjacent quaternary stereocenters. It is a known
precursor of the anti-HIV agent biyouyanagin A (8)12d and
is of significant current interest given that the biological
(13) Brogan, J. B.; Richard, J. E.; Zercher, C. K. Synth. Commun. 1995,
25, 587–593.
(14) Calter, M. A.; Sugathapala, P. M. Tetrahedron Lett. 1998, 39, 8813–
8816.
Org. Lett., Vol. 10, No. 24, 2008
5555

NaBH3CN to a mixture of fused hemiketals in 69% yield
over two steps and in 80:13:4:3 diastereoselectivity (deter-
mined by H NMR) in favor of the desired isomer 16
Scheme 4. Dihydrofuranone Formation from 10
1
(stereochemistry assigned by NOE studies),11 which was
cleanly isolated from the mixture. From unsaturated R-diazo-
ꢀ-ketoester 10, one-pot cross-metathesis/[2,3] sigmatropic
rearrangement and reduction of the resulting crude material
gave hemiketal 16 in 26% yield. Spirolactonization of the
hemiketal 16 using DBU15 gave crude spirolactone 17 which
was directly dehydrogenated using DDQ16 giving hypero-
lactone C (7) (42% over two steps), with data consistent with
the literature.11,12
In summary, we have demonstrated the ability of R-diazo-
ꢀ-ketoesters bearing an allylic ether tether to undergo
stereoselective cross-metathesis, thus expanding the range
of functional group compatibility of Grubbs’ catalyst to such
diazo compounds. The R-diazo-ꢀ-ketoesters have also been
shown to undergo one-pot cross-metathesis/[2,3] sigmatropic
rearrangement via oxonium ylides to access dihydrofuranones
diastereoselectively; the latter further demonstrating the
compatibility of Ru and Rh catalysis in a one-pot procedure.
Finally, a synthesis of the anti-HIV agent hyperolactone C
has been accomplished using cross-metathesis followed by
a diastereoselective tandem oxonium ylide formation and
[2,3] sigmatropic rearrangement sequence as key transforma-
tions.
[which smoothly underwent ylide formation-rearrangement
in 75% yield, but with erosion of diastereoselectivity (65:
35) compared to allyl ether 10],11 implying that the low
metathesis yields with the above gem-disubstituted oxygen-
ated olefins is not due to the phenyl group present in 10. No
cross-metathesis was observed with tert-butyl methacrylate,
but methacrolein proved encouraging, giving only the E-enal
14, albeit in 21% yield (Scheme 5).
Scheme 5. Hyperolactone C Synthesis
Acknowledgment. We thank the University of Oxford for
a full Clarendon Fund bursary award (to D.A.) and the
following people from Oxford (Chemistry Research Labora-
tory): Dr. B. Odell (NOE studies), R. Procter (mass spectra),
and Dr. D. Watkin and R. Thomas (X-ray crystallographic
analysis).
Supporting Information Available: Full experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL802334Y
(15) Klein, L. L.; Yeung, C. M.; Chu, D. T.; McDonald, E. J.; Clement,
J. J.; Plattner, J. J. J. Med. Chem. 1991, 34, 984–992.
(16) Semple, J. E.; Guthrie, A. E.; Joullie´, M. M. Tetrahedron Lett. 1980,
21, 4561–4564.
Other metathesis catalysts were less effective in the latter
reaction. Progressing enal 14 in the oxonium ylide formation-
rearrangement gave unstable aldehyde 15, best reduced using
5556
Org. Lett., Vol. 10, No. 24, 2008