Formal total synthesis of neopeltolide

Article abstract of DOI:10.1021/ol8001255

A concise synthesis of the core structure of the macrolide neopeltolide was develop featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leiqhton allylation and a Feringa-Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchin macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.

Full text of DOI:10.1021/ol8001255

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1239-1242
Formal Total Synthesis of Neopeltolide
Viktor V. Vintonyak and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received January 18, 2008
ABSTRACT
A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring.
Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa Minnaard asymmetric methyl cuprate addition to an
−
unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17
steps providing lactone 26 with an overall yield of 23%.
In 2007 the group of A. E. Wright described a novel mac-
rolide named neopeltolide (1) (Figure 1).1 The producing
deep-water sponge of the family Neopeltidae was collected
off the north Jamaican coast. Neopeltolide turned out to be
a very potent antitumor agent, inhibiting the proliferation of
various cell lines in the low nanomolar range. The structural
features of neopeltolide include a 14-membered macrolactone
ring that contains an ether bridge forming a tetrahydropyran
subunit. Moreover, there are six stereogenic centers. The
hydroxyl group at C5 is acylated with an oxazol- and a
carbamate-containing side chain. This substituent occupies
an axial position in the pyran ring. The side chain is identical
to the one in the macrolide leucascandrolide (3).2,3 Thus, one
can assume the same biological targets for these two
compounds. Further related natural products with a macro-
lactone part similar to neopeltolide include polycavernoside4,5
and callipeltoside.6-8
However, one should note that the C9-methyl group is not
sitting at a propionate position but rather at a former keto
function. The fascinating structure combined with the potent
(3) Total syntheses: (a) Hornberger, K. R.; Hamblett, C. L.; Leighton,
J. L. J. Am. Chem. Soc. 2000, 122, 12894-12895. (b) Kopecky, D. J.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123, 8420-8421. (c) Fettes,
A.; Carreira, E. M. Angew. Chem. 2002, 114, 4272-4275. Angew. Chem.,
Int. Ed. 2002, 41, 4098-4101. (d) Wang, Y.; Janjic, J.; Kozmin, S. A. J.
Am. Chem. Soc. 2002, 124, 13670-13671. (e) Paterson, I.; Tudge, M.
Angew. Chem. 2003, 115, 357-361. Angew. Chem., Int. Ed. 2003, 42, 343-
347. (f) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641-4644.
(g) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274-9283. (h)
Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833-6849. (i) Williams,
D. R.; Patnaik, S.; Plummer, S. V. Org. Lett. 2003, 5, 5035-5038. (j) Su,
Q.; Panek, J. S. Angew. Chem. 2005, 117, 1249-1251; Angew. Chem., Int.
Ed. 2005, 44, 1223-1225. (k) Van Orden, L. J.; Patterson, B. D.;
Rychnovsky, S. D. J. Org. Chem. 2007, 72, 5784-5793. (l) Ferrie´, L.;
Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2007, 9, 2461-2464.
(m) Su, Q.; Dakin, L. A.; Panek, J. S. J. Org. Chem. 2007, 72, 2-24.
(4) Isolation: Yamashita, M. Y.; Haddock, R. L.; Yasumoto, T. J. Am.
Chem. Soc. 1993, 115, 1147-1148.
(5) For some recent syntheses, see: (a) Fujiwara, K.; Murai, A.; Yotsu-
Yamashita, M.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 10770-10771.
(b) Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J. Am.
Chem. Soc. 2000, 122, 619-631. (c) Blakemore, P. R.; Browder, C. C.;
Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D.
J.; White, J. D. J. Org. Chem. 2005, 70, 5449-5460.
(6) Isolation: Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.;
Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085-11088.
(7) For a summary of total syntheses, see: Wittmann, V. Nachr. Chem.
Tech. Lab. 2002, 50, 841-845.
Two recent total syntheses, one by Panek9 and the other
by Scheidt et al.,10 showed the original structural assignment
to be partially wrong. Thus, the stereocenters at C11 and
C13 had to be revised. The various hydroxyl functions in
1,3-distance make it clear that neopeltolide is a polyketide.
(1) (a) Wright, A. E.; Botelho, J. C.; Guzma´n, E.; Harmody, D.; Linley,
P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod.
2007, 70, 412-416. (b) Wright, A. E.; Pomponi, S. A.; McCarthy, U.S.
Patent 7179828B2, 2007.
(2) Isolation: D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F.
HelV. Chim. Acta 1996, 79, 51-60.
(8) For some recent total syntheses, see: (a) Trost, B. M.; Gunzner, J.
L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396-10415. (b)
Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002,
124, 5654-5655. (c) Paterson, I.; Davies, R. D. M.; Heimann, A. C.;
Marquez, R.; Meyer, A. Org. Lett. 2003, 5, 4477-4480.
10.1021/ol8001255 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

biological activity prompted us to embark on a synthesis of
2. We conceived a strategy that would be flexible enough
to access analogs and derivatives that might help to identify
the biological target. Furthermore, analogs that could illum-
inate key structural features important for the activity were
planned. For example, analogs with a repositioned methyl
group, a strategy that we term propionate scanning, would
be desirable.
reaction would have to be used for the attachment of the
side chain. The Prins strategy leads to an aldehyde C and a
homoallylic alcohol D. The alcohol functions in the aldehyde
C should pose no big problems.16 A key question relates to
the introduction of the subunit with the methyl group. In
this regards, we chose a facial selective Michael addition
using the Feringa-Minnaard reaction.17,18 While this makes
the route somehow linear, we demonstrate in the following
that the conceived synthesis nevertheless is very concise.
The synthesis began with the 3-ketoester 4, which was
subjected to an enantioselelctive Noyori hydrogenation19,20
using (S)-BINAP-Ru(II) as chiral catalyst (Scheme 2).
(12) For some recent papers from the Rychnovsky group, see: (a) Jaber,
J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4679-4686.
(b) Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 15662-
15663. (c) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1589-
1591. (d) Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc.
2005, 127, 9939-9945. (f) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org.
Chem. 2006, 71, 3176-3183.
(13) For some recent papers from the Yadav group, see: (a) Yadav, J.
S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46, 2133-2136.
(b) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron Lett.
2006, 47, 4397-4401. (c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4937-4941. (d) Yadav, J. S.; Subba Reddy,
B. V.; Maity, T.; Narayana Kumar, G. G. K. S. Tetrahedron Lett. 2007,
48, 7155-7159. (e) Yadav, J. S.; Padmavani, B.; Reddy, B. V. S.;
Venugopal, C.; Rao, A. B. Synlett 2007, 2045-2048.
Figure 1. Structures of the related macrolides neopeltolide (2) and
leucascandrolide (3). The acyl side chains at C5 are identical in
both compounds.
(14) For recent papers from the Willis group, see: (a) Crosby, S. R.;
Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4,
577-580. (b) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.;
Willis, C. L. Org. Lett. 2002, 4, 3407-3410. (c) Barry, C. S. J.; Crosby, S.
R.; Harding, J. R.; Hughes, R. A.; King, C. D.; Parker, G. D.; Willis, C. L.
Org. Lett. 2003, 5, 2429-2432. (d) Barry, C. S.; Bushby, N.; Harding, J.
R.; Willis, C. L. Org. Lett. 2005, 7, 2683-2686. (e) Barry, C. S.; Bushby,
N.; Harding, J. R.; Hughes, R. A.; Parker, G. D.; Roe, R.; Willis, C. L.
Chem. Commun. 2005, 3727-3729. (f) Barry, C. S.; Elsworth, J. D.; Seden,
P. T.; Bushby, N.; Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett.
2006, 8, 3319-3322.
(15) For other recent papers describing the use of a Prins reaction, see:
(a) Marko´, I. E.; Bayston, D. J. Synthesis 1996, 297-304. (b) Cossey, K.
N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216-12217. (c) Overman,
L. E.; Velthuisen, E. J. Org. Lett. 2004, 6, 3853-3856. (d) Aubele, D. L.;
Wan, S.; Floreancig, P. E. Angew. Chem. 2005, 117, 3551-3554; Angew.
Chem., Int. Ed. 2005, 44, 3485-3488. (e) Epstein, O. L.; Rovis, T. J. Am.
Chem. Soc. 2006, 128, 16480-16481. (f) Lee, C.-H. A.; Loh, T.-P.
Tetrahedron Lett. 2006, 47, 1641-1644. (g) Chan, K.-P.; Seow, A.-H.;
Loh, T.-P. Tetrahedron Lett. 2006, 48, 37-41. (h) Ko, H. M.; Lee, D. G.;
Kim, M. A.; Kim, H. J.; Park, J.; Lah, M. S.; Lee, E. Tetrahedron 2007,
63, 5797-5805. (i) Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahedron 2007,
63, 7874-7878. (j) Reddy, M. S.; Narender, M.; Rao, K. R. Tetrahedron
2007, 63, 11011-11015. (k) Pham, M.; Allatabakhsh, A.; Minehan, T. G.
J. Org. Chem. 2008, 73, 741-744.
A synthesis has to address the formation of the pyran ring
and the creation of the region carrying the methyl group.
Our retrosynthesis is shown in Scheme 1. Thus, after opening
Scheme 1. Key Retrosynthetic Cuts for the Neopeltolide Core
Structure A, P ) Protecting Group
(16) For a recent review covering the synthesis of 1,3-diols, see: Bode,
S. E.; Wolberg, M.; Mu¨ller, M. Synthesis 2006, 557-588.
(17) For a review, see: Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. Acc.
Chem. Res. 2007, 40, 179-188.
(18) (a) Lo´pez, F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.;
Feringa, B. L. Angew. Chem. 2005, 117, 2812-2816; Angew. Chem., Int.
Ed. 2005, 44, 2752-2756. (b) Mazery, R. D.; Pullez, M.; Lo´pez, F.;
Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2005, 127, 9966-9967. (c) Harutyunyan, S. R.; Lopez, F.; Browne, W. R.;
Correa, A.; Pena, D.; Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2006, 128, 9103-9118. (d) van Summeren, R. P.;
Moody, D. B.; Feringa, B. L.; Minnaard, A. J. J. Am. Chem. Soc. 2006,
128, 4546-4547. (e) ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem.
Commun. 2007, 489-491. (f) Horst, B. t.; Feringa, B. L.; Minnaard, A. J.
Org. Lett. 2007, 9, 3013-3015.
of the lactone A, the seco acid B or a derivative thereof could
be further disconnected by considering a Prins reaction on
the pyran. The TFA-promoted Prins reaction would lead to
an equatorial 5-OH group.11-15 Accordingly, a Mitsunobu
(9) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S. Angew.
Chem. 2007, 119, 9371-9374; Angew. Chem., Int. Ed. 2007, 46, 9211-
9214.
(10) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc.
2008, 130, 804-805.
(11) For recent reviews, see: (a) Overman, L. E.; Pennington, L. D. J.
Org. Chem. 2003, 68, 7143-7157. (b) Diaz, D. D.; Miranda, P. O.; Padron,
J. I.; Martin, V. S. Curr. Org. Chem. 2006, 10, 457-476. (c) Pastor, I. M.;
Yus, M. Curr. Org. Chem. 2007, 11, 925-957.
(19) For a review, see: Noyori, R. Angew. Chem. 2002, 114, 2108-
2123. Angew. Chem., Int. Ed. 2002, 41, 2008-2022.
(20) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth.
1992, 71, 1-13; Organic Syntheses; Wiley: New York, 1998; Collect. Vol.
IX, pp 589-597. (b) King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven,
T. R. J. Org. Chem. 1992, 57, 6689-6691. (c) Geneˆt, J. P.; Ratovelomanana-
Vidal, V.; Can˜o, de Andrade, M. C.; Pfister, X.; Guerreiro, P.; Lenoir, J.
Y. Tetrahedron Lett. 1995, 36, 4801-4804. (d) Deng, L.-S.; Huang, X.-P.;
Zhao, G. J. Org. Chem. 2006, 71, 4625-4635.
1240
Org. Lett., Vol. 10, No. 6, 2008

Scheme 2. Synthesis of Aldehyde 16 via Leighton Allylation
of Aldehyde 7 and Asymmetric Methyl Cuprate Addition to
Enthioate 13; R ) TBDPS, Ar ) pBrC6H4
Scheme 3. Prins Cyclization for Formation of Pyran 19 and
Yamaguchi Macrolactonization of Hydroxy Acid 24 Leading to
the Core Structure 26 of Neopeltolide (2)
Silylation of the alcohol 5 produced ether 6 in almost
quantitative yield. This was followed by ester reduction using
DIBAL-H21 at -80 °C in dichloromethane leading to
aldehyde 7. Chain extension was performed with the Leigh-
ton reagent 8,22 containing (R,R)-1,2-diaminocyclohexane.
The alcohol function in the 1,3-anti-diol 9 was protected
using Meerwein’s salt in the presence of a proton sponge.23
With other conditions partial migration of the silyl group
was observed. In the 13C NMR spectrum of 10 there was no
other diastereomer visible, indicating the excellent selectivity
in the allylation reaction. Oxidative degradation of the double
bond of 10 led to aldehyde 11 that was extended to the
unsaturated thioester24 13 using the stabilized Wittig reagent
12. A conjugate addition reaction of methylmagnesium
bromide (1.2 equiv) to 13 in the presence of CuBr‚SMe2
(3.4 mol %) and the chiral diphosphine (S,R)-Josiphos25,26
14 (4 mol %) produced the decanoate 15 in high yield.18
Only one set of signals was observed for 15 in the 13C NMR
spectrum. Reduction of the thioester with Et3SiH in the
presence of Pd/C gave an almost quantitative yield of
aldehyde 16.
The homoallylic alcohol 18 required for the Prins reaction
was available by allylation of the aldehyde27 17 with the
Leighton reagent (S,S)-8 (Scheme 3). For the crucial Prins
reaction the homoallylic alcohol 18 and aldehyde 16 were
(21) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 3, 619-
620.
(22) (a) Kubota, K.; Leighton, J. L. Angew. Chem. 2003, 115, 976-
978; Angew. Chem., Int. Ed. 2003, 42, 946-948. (b) Berger, R.; Rabbat,
P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596-9597. (c)
Zhang, X.; Houk, K. N.; Leighton, J. L. Angew. Chem. 2005, 117, 960-
963; Angew. Chem., Int. Ed. 2005, 44, 938-941.
(23) Diem, M. J.; Burow, D. F.; Fry, J. L. J. Org. Chem. 1977, 42, 1801-
1802.
(24) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50,
709-710.
(25) For a review, see: (a) Arraya´s, R. G.; Adrio, J.; Carretero, J. C.
Angew. Chem. 2006, 118, 7836-7878; Angew. Chem., Int. Ed. 2006, 45,
7674-7715.
(26) For the preparation of Josiphos ligands, see: (a) Arimoto, F. S.;
Haven, A. C., Jr. J. Am. Chem. Soc. 1955, 77, 6295-6297. (b) Gokel, G.
W.; Ugi, I. K. J. Chem. Educ. 1972, 49, 294-296. (c) Sihler, R.; Werz, U.;
Brune, H. A. J. Organomet. Chem. 1989, 368, 213-221. (d) Marquarding,
D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970,
92, 5389-5393. (e) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.;
Nagashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.;
Yamamoto, K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138-1151.
(f) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani,
A. J. Am. Chem. Soc. 1994, 116, 4062-4066.
Org. Lett., Vol. 10, No. 6, 2008
1241

reacted in dichloromethane in the presence of trifluoroacetic
acid (10 equiv). This led to the pyran in 72% yield. Besides
the major product 20, the formation of a small amount of
another isomer (major/minor ) 8:1) was observed. The
formation of the desired tetrahydropyran can be envisioned
to proceed via oxonium ion F with an all equatorial
orientation of the substituents in the chairlike transition state.
A few simple functional group manipulations, i.e., basic
cleavage of the trifluoroacetate, MOM protection of the
resulting alcohol 20, and debenzylation, led to primary
alcohol 22. Oxidation of 22 using a well-established sequence
consisting of Dess-Martin and sodium chlorite oxidation28
furnished acid 23. Fluoride-induced cleavage of the silylether
led to seco-acid 24. Employing classical Yamaguchi condi-
tions,29,30 the acid cyclized in high yield to macrolactone 25.
At this stage the minor isomer resulting from the Prins
reaction could be separated. A final cleavage of the MOM-
protecting group completed the synthesis of the neopeltolide
core structure 26 {[R]20D ) +18.4 (c 0.1, CHCl3)}. The NMR
spectra of 26 perfectly matched the one reported by Scheidt
et al.10
In conclusion, an efficient synthesis of the macrolactone
part of neopeltolide could be developed. Key steps include
two Leighton allylations. One led to the anti-diol 9, and the
other one produced the homoallylic alcohol 18. The fact that
the chiral diamine can be recovered makes this method very
attractive for large-scale allylations. The methyl-bearing
stereocenter (C9) came from an asymmetric methyl cuprate
addition to the unsaturated thioester 13 using the Feringa-
Minnaard method. Pyran formation could be achieved by
classical TFA-mediated Prins reaction between aldehyde 16
and homoallylic alcohol 18. A Yamaguchi macrolactoniza-
tion eventually led to the core macrolactone 26 of the novel
macrolide neopeltolide (2). Since lactone 26 is an advanced
intermediate in the total synthesis of neopeltolide by Scheidt
et al., our work represents a formal total synthesis of this
natural product. Starting from keto ester 4, the synthesis of
lactone 26 required 17 steps in the longest linear sequence
and produced lactone 26 in 23% overall yield. In this regard
it compares favorably with the other known routes.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. In addition, a graduate
fellowship for V.V.V. from the state Baden-Wu¨rttemberg
(LGFG) is acknowledged as well. We also thank Marcellino
Cala` (Universita¨t Tu¨bingen) for his contribution.
(27) (a) Wang, Y.; Farquhar, D. J. Med. Chem. 1991, 34, 197-203. (b)
D´ıez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Mene´ndez, J.
C.; Organ, H. M.; White, A. D.; Banks, B. J. Tetrahedron 1992, 48, 7899-
7938. (c) Azzena, F.; Calvani, F.; Crotti, P.; Gardelli, C.; Macchia, F.;
Pineschi, M. Tetrahedron 1995, 51, 10601-10626. (d) We prepared this
aldehyde by DIBAL-H reduction of the nitrile resulting from Michael
addition of benzylalcohol to acrylonitrile; see Supporting Information.
(28) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175-
1176. (b) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(29) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(30) (a) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237-4313.
(b) Parenty, A.; Moreau, X.; Campagne, J. M. Chem. ReV. 2006, 106, 911-
939.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8001255
1242
Org. Lett., Vol. 10, No. 6, 2008