The asymmetric Maitland-Japp reaction and its application to the construction of the C1-C19 bis-pyran unit of phorboxazole B

Article abstract of DOI:10.1021/ol102860r

The synthesis of the C1-C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an asymmetric Maitland-Japp reaction and a second Maitland-Japp resolution/cyclization reaction. The longest linear sequence w

Full text of DOI:10.1021/ol102860r

ORGANIC
LETTERS
2011
Vol. 13, No. 4
624–627
The Asymmetric Maitland-Japp Reaction
and Its Application to the Construction of
the C1-C19 Bis-pyran Unit of
Phorboxazole B
Paul A. Clarke,*,† Soraia Santos,† Nimesh Mistry,† Laurence Burroughs,† and
Alexander C. Humphries‡
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U.K., and
Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road,
Loughborough, Leicestershire, LE11 5RH, U.K.
paul.clarke@york.ac.uk
Received November 26, 2010
ABSTRACT
The synthesis of the C1-C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an
asymmetric Maitland-Japp reaction and a second Maitland-Japp resolution/cyclization reaction. The longest linear sequence was 14 steps, and
the C1-C19 bis-pyran unit was formed in an impressive 10.4% yield.
The tetrahydropyran (THP) unit is present in a vast
array of structurally complex and biologically active nat-
ural products. In recent years there has been renewed
interest in developing new and more efficient routes to
THPs in order to expedite the syntheses of these natural
products.1 Recent research in our group has focused on the
development of a one-pot, multicomponent route to highly
substitutedTHPs, and werecently achieved this via a THP-
forming strategy based on the long-forgotten Maitland-
Japp reaction.2 However, in this earlier work, the goal of
developing a general asymmetric Maitland-Japp reaction
eludedus. Morerecent workona versionofthe Maitland-
Japp reaction which utilized diketene as a nucleophile
(Scheme 1) provided us with the opportunity to rectify
this deficiency. In the ‘diketene Maitland-Japp’ reaction
the mono-γ-titanium enolate of a β-ketoester is formed by
the nucleophilic ring-opening of diketene via ligand trans-
fer from the activating Lewis acid. This ‘nucleophile
generated enolate’ can then add to an aldehyde or imine
to generate aldol2e or Mannich-like3 products respectively.
Initially eitherTiCl4 orTi(iOPr)4 were used asa Lewisacid.
† University of York.
‡ AstraZeneca R&D Charnwood.
(1) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045–53.
(2) (a) Japp, F. R.; Maitland, W. J. Chem. Soc. 1904, 85, 1473–89. (b)
Clarke, P. A.; Martin, W. H. C. Org. Lett. 2002, 4, 4527–9. (c) Clarke,
P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J.
Chem. Commun. 2005, 1061–3. (d) Clarke, P. A.; Martin, W. H. C.;
Hargreaves, J. M.; Wilson, C.; Blake, A. J. Org. Biomol. Chem. 2005, 3,
3551–63. (e) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem.
2007, 9, 438–40.
(3) Clarke, P. A.; Zaytsev, A. V.; Morgan, T. W.; Whitwood, A. C.;
Wilson, C. Org. Lett. 2008, 10, 2877–80.
r
10.1021/ol102860r
Published on Web 01/19/2011
2011 American Chemical Society

Table 1. Asymmetric Addition of Diketene to Aldehydes
Scheme 1. Asymmetric Diketene Maitland-Japp Reaction
entry
ligand
RCHO
1 yield (%)a
1 % eeb
a
b
c
d
e
f
3a
Ph
44
35
51
47
47
45
45
51
47
52
47
61
82
64
85
71
59
80
75
80
87
86
71
71c
p-MeOC6H4
p-NO2C6H4
Pr
iPr
3b
Ph
g
h
i
CH2CHdCHMe
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
3c
3d
3e
3f
j
k
l
a Isolated yield after 72 h. b Enantioselectivities were determined
either by 1H NMR shift reagent experiments with tris[3-(heptaflu-
oropropylhydroxy-methylene)-d-camphorato] europium(III) or by re-
duction to the anti-diol and chiral HPLC analysis. See Supporting
Information for details. c ent-1 was formed.
Inverting the sense of the stereocenters on the imine
nitrogen resulted in the opposite enantiomer of the δ-
hydroxy-β-ketoester being formed (entry l). In cases
where the δ-hydroxy-β-ketoester was cyclized to a THP
and the THP was crystalline, recrystallization increased the
enantiopurity of the THP to >95% ee.2d Encouraged by the
development of an asymmetric Maitland-Japp reaction and
by the observation that the enantioselectivities of the resul-
tant THPs could be enhanced by recrystallization, it was
decided to attempt to apply this asymmetric Maitland-
Japp reaction to the synthesis of the C1-C19 bis-pyran unit
of the phorboxazoles.
However, this generated carboxylic acids or isopropyl
esters as products respectively, which we considered to be
less useful for the synthesis of THPs. We noted, however,
that the addition of an external alcohol nucleophile, such
as methanol, to the enolate generating reaction enabled
the formation of more synthetically useful methyl esters
without detriment to the yield of the reaction. The use of
Ti(iOPr)4 as a Lewis acid also provided us with the
opportunity to screen a number of chiral ligands and to
monitor the effect these had on the enantioselectivity of the
reaction. As we had previously shown that the enantiomeric
integrity of the aldol product was not eroded by the
Maitland-Japp cyclization conditions,2d we were hopeful
that an asymmetric one-pot, multicomponent THP-form-
ing reaction could be developed.
After a number of different ligand types failed we were
pleased to find that the addition of a chiral Schiff’s
base ligand of type 3 to the initial enolate-forming/alde-
hyde addition reaction generated the desired δ-hydroxy-β-
ketoester in an enantioenriched form (Scheme 1).4 As
can be seen from Table 1 a range of aromatic, aliphatic,
branched aliphatic, and heteroatom-containing aldehydes
could all be used in the reaction (entries a, d, e, and h
respectivly). The enantioselectivities in general tended to
be higher for aromatic aldehydes than aliphatic aldehydes
(entries c and d). While the size of the substituent at the
ligand’s stereogenic center did not seem to have much
effect on the enantioselectivity of the reaction (entries a
and f), substitution on the ligand’s nonphenolic aryl group
did increase the enantioselectivity slightly (entries h, i, and j).
Figure 1. Phorboxazole A, 4: R1 = H, R2 = OH; phorboxazole
B, 5: R1 = OH, R2 = H.
In 1995, Searle and Molinski reported the isolation of
phorboxazoles A and B (Figure 1), C13 epimers, from the
marine sponge Phorbas sp. endemic to the western coast of
Australia.5 These natural products have become a syn-
thetic target with great interest due to their potent anti-
cancer, antifungal,5,6 and antibiotic7 activity. In fact, these
(5) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,
8126–31.
(4) (a) Hiyashi, M.; Inouse, T.; Oguni, N. J. Chem. Soc., Chem.
Commun. 1994, 341–2. (b) Hayashi, M.; Inouse, T.; Miyamoto, Y.;
Oguni, N. Tetrahedron 1994, 50, 4385–98. (c) Hayashi, M.; Inoue, T.;
Miyamoto, Y.; Oguni, N. Tetrahedron: Asymmetry 1995, 6, 1833–6.
(6) (a) Searle, P. A.; Molinki, T. F.; Brzezinski, L. J. J. Am. Chem.
Soc. 1996, 118, 9422–3. (b) Molinski, T. F. Tetrahedron Lett. 1996, 37,
7879–80.
Org. Lett., Vol. 13, No. 4, 2011
625

The phorboxazole skeleton consists of six rings includ-
ing two 2,4-disubstituted oxazoles and four tetrahydro-
pyran (THP) units, as well as 15 stereogenic centers
organized into a macrolide lactone (C1-C26) and a side
chain substructure (C27-C46). Not surprisingly, the
novel architecture combined with the impressive bioactiv-
ity has attracted wide attention in the synthetic com-
munity.7,9-12
Scheme 2. Retrosynthetic Analysis of the Bis-pyran Units of the
Phorboxazoles
As such we were attracted to the possibility that our
methodology could be used to construct the THP rings of
the phorboxazoles in an expedient manner. To this end a
retrosynthetic plan was developed for the synthesis of the
C1-C19 bis-pyran fragment of phorboxazole B (Scheme 2).
Scheme 3. Synthesis of the First Tetrahydropyran 15
compounds exhibit extraordinary cytotoxic activity (GI50
< 8 Â 10-10 M) against the entire panel of human tumor
cell lines held at the National Cancer Institute. Together
with spongistatins,8 phorboxazoles are the most potent
naturally occurring cytotoxic agents yet discovered. Fur-
thermore, due to restricted access to the sponge, total
synthesis is the solution to the phorboxazoles’ limited
availability problem.9
(7) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 10942–53.
(8) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.;
Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302–4.
(9) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597–8.
Our synthesis of the C1-C19 fragment of the phorbox-
azoles began with an asymmetric Maitland-Japp reaction
of diketene with aldehyde 11 as the first aldehyde and
oxazole aldehyde 10 as the second aldehyde cyclization
partner (Scheme 3). This generated a mixture of 12 and 13
in 52% and 27% yields respectively, with an enantiomeric
excess of 73%. We have shown that the keto-cis and enol-
trans forms of the THPs generated in the Maitland-Japp
reaction are in equilibrium with each other under Lewis
acidic conditions,2c,d,13and so we were able to separate 12
from 13 and re-equilibrate 13 to a 2:1 mixture of 12:13 by
use of Yb(OTf)3 in CH2Cl2. In this way the yield of 12 was
increased to 70% after one re-equilibration with no loss of
its enantiomeric integrity. Tetrahydropyran-4-one 12 was
decarboxylated under microwave conditions, the ketone
was reduced with NaBH4 to afford the stereochemistry
required for the synthesis of 5, and the free hydroxyl group
protected asa TIPS ether to yield 14. The benzyl ether of 14
was removed with H2 over 10% Pd/C and the primary
alcohol oxidized with Dess-Martin periodinane to gen-
erate aldehyde 15, which we hoped would be a suitable
(10) For total syntheses of phorboxazole A, see: (a) Smith, A. B., III;
Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001,
123, 4834–36. (b) Gonzalez, M. A.; Pattenden, G. Angew. Chem., Int. Ed.
2003, 42, 1255–8. (c) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark,
M. P.; Berliner, M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42,
1258–62. (d) Pattenden, G.; Gonzalez, M. A.; Little, P. B.; Milan, D. S.;
Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biolmol. Chem. 2003, 1,
4173–208. (e) Smith, A. B., III; Razler, T. M.; Ciavarri, J. P.; Hirose, T.;
Ishikawa, T. Org. Lett. 2005, 7, 4399–402. (f) White, J. D.; Kuntiyong,
P.; Tae, H. L. Org. Lett. 2006, 8, 6039–42. (g) White, J. D.; Kuntiyong,
P.; Tae, H. L. Org. Lett. 2006, 8, 6043–6. (h) Smith, A. B., III; Razler,
T. M.; Ciavarri, J. P.; Hirose, T.; Ishikawa, T.; Meis, R. M. J. Org.
Chem. 2008, 73, 1192–200.
(11) For total syntheses of phorboxazole B, see: (a) Evans, D. A.;
Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed.
2000, 39, 2533–6. (b) Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed.
2000, 39, 2536–40. (c) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J.
J. Am. Chem. Soc. 2000, 122, 10033–46. (d) Li, D.-R.; Zhang, D.-H.;
Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-
S.; Lin, G.-Q. Chem.;Eur. J. 2006, 12, 1185–204. (e) Lucas, B. S.;
Gopalsamuthiram, V.; Burke, S. D. Angew. Chem., Int. Ed. 2007, 46,
769–72.
(12) For syntheses of the bis-pyran fragments which have not yet
resulted in the report of a completed synthesis, see: (a) Wolbers, P.;
Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905–14. (b) Greer, P. B.;
Donaldson, W. A. Tetrahedron 2002, 58, 6009–18. (c) Paterson, I.;
Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749–54. (d) Yadav,
J. S.; Rajaiah, G. Synlett 2004, 1537–40. (e) Paterson, I.; Steven, A.;
Luckhurst, C. A. Org. Biomol. Chem. 2004, 2, 3026–38. (f) Vitale, J. P.;
Wolckenhauer, S. A.; Do, N. M.; Rychnovsky, S. D. Org. Lett. 2005, 7,
3255–58. (g) Yadav, J. S.; Prakash, S. J.; Gangadhar, Y. Tetrahedron:
Asymmetry 2005, 16, 2722–28. (h) Kartika, R.; Taylor, R. E. Angew.
Chem., Int. Ed. 2007, 46, 6874–77.
(13) (a) Clarke, P. A.; Martin, W. H. C. Tetrahedron Lett. 2004, 45,
9061–3. (b) Clarke, P. A.; Martin, W. H. C. Tetrahedron 2005, 61,
5433–8.
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Org. Lett., Vol. 13, No. 4, 2011

substrate for the formation of the second THP unit via the
Maitland-Japp reaction.
catalyzed addition of Chan’s diene to benzyloxy acetalde-
hyde, giving 16 in 90% yield and with a 99% ee. The
δ-hydroxy-β-ketoester 16 was subjected to our tandem
Maitland-Japp cyclization protocol using 15 (73% ee)
as the aldehyde partner. The 1H NMR of the crude
reaction mixture was rather complex at this stage, so the
mixture of diastereomers was subjected to microwave
mediated decarboxylation. Pleasingly, however, flash col-
umn chromatographic purification resultedin the isolation
of17in68% yield, 99% ee(actually84% yieldbased onthe
73% ee of aldehyde 15) and some of the diastereomer
resulting from the minor enantiomer of 15 in 8% yield.
This demonstrates that the Maitland-Japp reaction can
be used not only to form stereochemically complex bis-
THP units but also an efficient method for the constructive
resolution of a starting aldehdye, efficiently generating the
complex bis-THP unit as a single enantiomer and in
excellent yield. Removal of the benzyl group of 17 and
Wittig olefination generated alcohol 18, which was con-
verted to the triflate and displaced with the dianion of
N-phenyl propynamide,11c to give 19. The relatively acidic
amide NH was protected with a Boc-group, and then the
oxazole’s methyl group was brominated by the formation
of the anion with LDA at -78 °C and treatment with NBS.
This yielded the C1-C19 bis-pyran fragment of phorbox-
azole B 20, with functionality at either end to allow for
coupling to the other fragments of the natural product.
In summary we have developed a one-pot, multicompo-
nent asymmetric version of the Maitland-Japp reaction
and applied it to the synthesis of the C1-C19 fragment 20
of phorboxazole B 5. The longest linear sequence was 14
steps, and the overall yield was calculated to be 10.4%
which compares favorably to the previously reported syn-
theses of this fragment.10-12 The success of our strategy
has spurred us on to attempt a total synthesis of phorbox-
azole B 5, and this shall be reported in due course.
Unfortunately, none of the THPs (12 to 15) were crystal-
line and so we were unable to use recrystallization to
increase the enantiomeric excess of 15 before attempting
thesecond Maitland-Japp reaction. Additionally, the best
asymmetric Maitland-Japp reaction with benzyloxy acet-
aldehyde generated product in 87% ee which would mean
that such a Maitland-Japp reaction would result in a
complex mixture of multiple diastereomers in both enan-
tiomeric series, requiring separation. As this was not an
attractive proposition we decided to react 15 (73% ee) with
a δ-hydroxy-β-ketoester 16 of enantiomeric purity and
then to separate the two diastereomers which would be
formedinabouta 7.7:1ratio. Itwas envisaged thatthisfirst
example of a resolving Maitland-Japp reaction could be
achieved by the use of Evans’ Cu(pybox) catalyzed addi-
tion of Chan’s diene to benzyloxy acetaldehyde.11c Pleas-
ingly, this would also be in keeping with our earlier work
on the Maitland-Japp reaction which utilized Chan’s
diene as a nucleophile instead of diketene.2c,d,13
Scheme 4. Synthesis of the C1-C19 Bis-pyran Unit 20
Acknowledgment. We thank EPSRC (Grant EP/C514-
750/1) and AstraZeneca for funding and Dr. John Carey
(GSK, Tonbridge) for generous donations of oxazole
aldehyde 10.
Supporting Information Available. Full experimental
1
procedures, characterization, and copies of H and 13C
NMR of all new compounds is included. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Thus our synthesis of the C1-C19 fragment of 5
continued (Scheme 4) with the Evans Cu(R, R-pybox)
Org. Lett., Vol. 13, No. 4, 2011
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