Regioselective lipase-catalyzed acylation of 41-desmethoxy-rapamycin without vinyl esters

Article abstract of DOI:10.1016/j.tetlet.2010.08.020

Selective lipase-catalyzed acylation of 41-desmethoxyrapamycin has been achieved with a quaternary carboxylic acid avoiding the use of vinyl ester activation. Among the acyl donors investigated, the novel butanedione-monooxime and the N-acetylhydroxamate ester proved to be the most efficient donors, comparable in reactivity to the undesired vinyl ester and allowing selective, preparative acylation on gram scale in excellent yields. These new donors are proposed as sustainable and process-friendly alternatives to the widely used vinyl ester substrate activation in lipase-catalyzed acylations of secondary alcohols.

Full text of DOI:10.1016/j.tetlet.2010.08.020

Tetrahedron Letters 51 (2010) 5511–5515
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective lipase-catalyzed acylation of 41-desmethoxy-rapamycin
without vinyl esters
Thomas Storz a, , Jianxin Gu a, Bogdan Wilk a, Eric Olsen b
⇑
a Pfizer Worldwide R&D, Chemical Research & Development, Eastern Point Road, Groton, CT 06340, USA
b Pfizer Worldwide R&D, Analytical Sciences, 401 N. Middletown Rd., Pearl River, NY 10965, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective lipase-catalyzed acylation of 41-desmethoxyrapamycin has been achieved with a quaternary
carboxylic acid avoiding the use of vinyl ester activation. Among the acyl donors investigated, the novel
butanedione-monooxime and the N-acetylhydroxamate ester proved to be the most efficient donors,
comparable in reactivity to the undesired vinyl ester and allowing selective, preparative acylation on
gram scale in excellent yields. These new donors are proposed as sustainable and process-friendly alter-
natives to the widely used vinyl ester substrate activation in lipase-catalyzed acylations of secondary
alcohols.
Received 1 June 2010
Revised 4 August 2010
Accepted 7 August 2010
Available online 11 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Rapamycin (sirolimus, Rapamune), a 31-member polyketide
macrolide1a,b with immunosuppressive1c and antiproliferative
properties,1d and its analogs have been extensively reviewed.2
The two most prominent7 derivatives, temsirolimus (CCI-779)3
and everolimus (RAD001)4 (Fig. 1), are mTOR inhibitors5 used in
cancer therapy.6,8
Evidently, as all rapamycin derivatives currently approved
(temsirolimus, everolimus) for human therapy or in clinical trials
(Ridaforolimus) are 42-O-substituted molecules, the ability to
carry out selective modifications at/of the C42-hydroxyl is an
important asset.10 A Wyeth group had reported regioselective
lipase-catalyzed acylation of the 42-OH group in Rapamycin via
OH
OH
O
OH
42
O
42
O
O
OH
42
O
OMe
OMe
OMe
O
O
OH
O
OH
O
OH
N
O
N
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
HO
HO
Rapamycin (sirolimus)
CCI 779 (temsirolimus)
RAD 001 (everolimus)
Figure 1.
⇑
Corresponding author. Address: Pfizer Worldwide R&D, Pharmaceutical Sciences, Chemical Research & Development, Eastern Point Road, Groton, CT 06340, United States.
Tel.: +1 860 715 2190; fax: +1 860 441 5540.
E-mail address: thomas.storz@pfizer.com (T. Storz).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.020

5512
T. Storz et al. / Tetrahedron Letters 51 (2010) 5511–5515
OH
O
OH
42
OH
O
41
?
O
O
O
A
O
O
OH
N
O
O
O
OH
O
O
O
O
N
O
O
O
HO
O
O
O
O
O
O
HO
A
41-Desmethoxy-
rapamycin
B
from fermentation
(S. hygroscopicus)
ref [9]
41-Desmethoxy-
temsirolimus
ref [20]
Figure 2.
the Maillard/Wong enol ester activation method11 for a number of
different carboxylic acids, enabling the efficient conversion of rap-
amycin into temsirolimus12 (compare Fig. 1).13
A serious drawback of this vinyl ester methodology lies in the
stoichiometric generation of acetaldehyde.14 The low boiling point
(21 °C) and flash point (À40 °C) of acetaldehyde and the explosive
properties of acetaldehyde-air mixtures15 present significant pro-
cess obstacles. Also, synthesis of hindered vinyl ester donors typi-
cally requires the use of excess vinyl acetate at reflux temperature
and its subsequent distillative removal,16,17 another safety hazard
due to the potential of vinyl acetate to undergo exothermic poly-
merization in the gas phase18a and the polymerization hazard of
OH
42
O
O
O
O
lipase PS (Amano)
5A mol sieves
O
O
OH
N
O
TBME, 42 oC, 20 h
O
HO
O
O
O
O
O
O
O
OH
N
O
activated ester
(1.5 eq.)
O
HO
O
O
O
O
O
[50 mg scale]
O
O
+
(control reaction)
>95%
10%
O
O
[assay yields]
O
O
+
O
O
O
O
O
X
no reaction
15%
+
O
O X = H, F, Cl
X
X
O
O
+
+
N
O
O
O
O
O
decomposition
N
O
N
Scheme 1.

T. Storz et al. / Tetrahedron Letters 51 (2010) 5511–5515
5513
OH
O
O
O
42
O
O
lipase PS (Amano)
5A mol sieves
O
O
OH
N
O
TBME, 42 oC, 20 h
O
HO
O
O
O
O
O
O
O
OH
N
activated ester
O
HO
O
O
O
O
(1.5 eq.)
O
O
O
[50 mg scale]
(control reaction)
+
O
O
95%
C
A
lipase PS "Amano" IM
(Burkholderia cepacia)
Lipozyme TL IM
(Thermomyces lanuginosus)
[assay yields]
25%
[assay yields]
O
N
O
+
+
N
N
2
3
O
O
O
O
12%
O
O
n.d.
30%
O
O
4
5
NC
N
+
80%
O
45%
O
COOEt
O
O
O
H
+
+
50%
55%
80%
86%
N
O
O
O
O
O
6
N
O
O
Scheme 2.
vinyl compounds in general.18b Published reports on scale-up of
selective vinyl ester-mediated acylations are therefore very
scarce.19
Our investigation focused on finding a benign and scalable acyl
donor for selective acylation of 41-desmethoxy-rapamycin A to the
recently disclosed, biologically active rapamycin derivative 41-des-
methoxy temsirolimus20 B (Fig. 29,20).
We initially evaluated a number of obvious vinyl ester substi-
tutes, such as the corresponding isopropenyl ester21 2, the trihalo-
ethyl esters22 3/4, and a few other activated ester derivatives
depicted in Scheme 1.
Disappointingly, all of them were significantly inferior to the vi-
nyl ester control reaction under the same conditions.12 Surpris-
ingly, there was a large rate difference between the vinyl and the
isopropenyl ester reactions (entries 1 and 2).23
catalyzed acylation of a primary hydroxyl group (nucleoside deriv-
ative) carried out on pilot plant scale by a Schering–Plough group a
few years ago.25 Surprisingly, the intriguing reports of Schowen
et al.,26 Pratt et al.,27 and Demuth et al.28 on N-peptidyl-
O-acylhydroxylamines, inhibitors of several classes of proteases
(via irreversible acylation of a SER-hydroxy group in the active cen-
ter of the enzyme), had been known for some time without trigger-
ing any curiosity in the potential use of this activation principle for
lipase-catalyzed acylations.29 An initial screen with the acetone
oxime ester 3 and a number of additional oximates (2, 4, 6) as well
as the N-acetylhydroxamate ester 5 with two selected, immobi-
lized lipases was conducted (Scheme 2).
The oxime esters 4 and 6 showed promising activity surpassing
that of the known acetone oxime ester (3). More efficient initial
conversions were observed with the T. lanuginosus lipase compared
to the B. cepacia lipase, the benchmark enzyme from the earlier vi-
nyl ester study.12 Remarkably, the hydroxamate 5 also showed acyl
donor activity better than the acetone oxime ester 3. Little is
known on the impact of oxime ester structure on acylation effi-
ciency in lipase-catalyzed reactions,30 whereas N-acylhydroxa-
mates such as 6 have not previously been evaluated as acyl
donors in enzyme-catalyzed reactions.29
Since some initial reactivity was seen with the N-hydoxysuc-
cinmidyl ester (entry 4), we decided to expand this structural mo-
tive into leaving groups that would not be basic enough to cause
decomposition of the sensitive des methoxyrapamycin starting
material, such as seen with the imidazolide (entry 5) and a number
of nucleophilic catalysts also tried in conjunction with simple alkyl
and a number of different haloalkyl esters (data not shown)
.
The acetoneoxime active ester method24 came to mind, espe-
cially since this active ester had been used in a selective, lipase-
The two oxime esters 3 and 6 as well as the hydroxamate ester 5
were investigated further in a proof-of-concept study with immo-
bilized T. lanuginosus and B. cepacia lipases in preparative gram-
scale experiments (Scheme 3). The butanedione(mono)oxime ester
6 and the N-acetylhydroxamate ester 5 emerged as the most prom-
ising candidates for further development. Interestingly, for the
Rapamycin is rather labile to base; prolonged heating in the presence of a weak
base, even at low concentration, leads to decomposition, the major side-product being
the lactone ring-opened product (i.e., ‘‘seco-rapamycin”).

5514
T. Storz et al. / Tetrahedron Letters 51 (2010) 5511–5515
OH
2. (a) Smith, A. B.; Condon, S. M.; McCauley, J. A. Acc. Chem. Res. 1998, 31, 31; (b)
O
42
O
Dumont, F. J.; Su, Q. X. Life Sci. 1995, 58, 373; (c) Mann, J. Nat. Prod. Rep. 2001,
18, 417; (d) Pallet, N.; Beaune, P.; Legendre, C.; Anglicheau, D. Ann. Biol. Clin.
2006, 64, 107; (e) Mita, M. M.; Mita, A.; Rowinsky, E. K. Cancer Biol. Ther. 2003,
2, S169; (f) Ballou, L. M.; Lin, R. Z. J. Chem. Biol. 2008, 1, 27; (g) Graziani, E. I. Nat.
Prod. Rep. 2009, 26, 602.
O
O
biocatalyst
4/5Å mol sieves
O
O
OH
N
O
º
TBME, 42 C, 60 h
O
HO
O
O
O
O
O
O
O
OH
N
O
3. (a) Elit, L. Curr. Opin. Invest. Drugs 2002, 3, 1249; (b) Mounier, N.; Vignot, S.;
Spano, J.-P. Bull. Cancer 2006, 93, 1139; (c) Rini, B.; Kar, S.; Kirkpatrick, P. Nat.
Rev. Drug Disc. 2007, 6, 599.
4. (a) Dumont, F. J. Curr. Opin. Invest. Drugs 2001, 2, 1220; (b) Chapman, T. M.;
Perry, C. M. Drugs 2004, 64, 861; (c) Houghton, P. J. Clin. Cancer Res. 2010, 16,
1368.
5. (a) Konings, I. R. H. M.; Verweij, J.; Wiemer, E. A. C.; Sleijfer, S. Curr. Cancer
Drug Targets 2009, 9, 439; (b) Ponticelli, C. J. Nephrol. 2004, 17, 762; (c)
Easton, J. B. Oncogenomics Handbook 2005, 553; (d) Dowling, R. J. O.;
Topisirovic, I.; Fonseca, B. D.; Sonenberg, N. Biochim. Biophys. Acta, Prot.
Proteom. 2010, 1804, 433; (e) Sudarsanam, S.; Johnson, D. E. Curr. Opin. Drug
Disc. Dev. 2010, 13, 31.
O
O
O
HO
O
O
O
O
O
N
O
O
1.9 eq.
3
1g scale
C
A
isolated yield (chromat.)
Lipozyme TL IM
41%
(Thermomyces lanuginosus)
Lipase PS "Amano" IM
55%
(Burkholderia cepacia)
O
O
6. Sirolimus and Everolimus are also approved for use in transplant medicine, see:
(a) Campistol, J. M.; Cockwell, P.; Diekmann, F.; Donati, D.; Guirado, L.;
Herlenius, G.; Mousa, D.; Pratschke, J.; San Millan, J. C. R. Transplant Int. 2009,
22, 681; (b) Ma, A.; Ouyang, J.; Chen, H. Can. Med. Chem. Rev. 2005, 2, 429; (c)
Kapoor, A.; Figlin, R. A. Cancer 2009, 115, 3618; (d) Ravaud, A.; Wallerand, H.;
Culine, S.; Bernhard, J.-C.; Fergelot, P.; Bensalah, K.; Patard, J.-J. Europ. Urol.
2008, 54, 315; (e) Wysocki, P. J. Exp. Rev. Mol. Diagnost. 2009, 9, 231.
7. Two more derivatives are either in clinical trials (ridaforolimus) or clinical
usage (zotarolimus) (a) Ridaforolimus (Merck/Ariad) (AP23573; MK-8669;
formerly known as Deforolimus, in Ph. III): Mita, M. M.; Mita, A. C.; Chu, Q.
S.; Rowinsky, E. K.; Fetterly, G. J.; Goldston, M.; Patnaik, A.; Mathews, L.; Ricart,
A. D.; Mays, T.; Knowles, H.; Rivera, V. M.; Kreisberg, J.; Bedrosian, C. L.; Tolcher,
A. W. J. Clin. Oncol. 2008, 26, 361; (b) Zotarolimus (ABT-578, Abbott, in drug-
eluting cardiac stents): Brugaletta, S.; Burzotta, F.; Sabate, M. Exp. Opin.
Pharmacother. 2009, 10, 1047.
N
O
O
1.7 eq.
6
O
Lipozyme TL IM
94%
95%
(Thermomyces lanuginosus)
Lipase PS "Amano" IM
(Burkholderia cepacia)
O
O
H
N
O
O
1.9 eq.
O
5
Lipozyme TL IM
75%
48%
(Thermomyces lanuginosus)
Lipase PS "Amano" IM
(Burkholderia cepacia)
8. Yuan, R.; Kay, A.; Berg, W. J.; Lebwohl, D. J. Hematol. Oncol. 2009, 2, 45.
9. Lowden, P. A. S.; Böhm, G. A.; Metcalfe, S.; Staunton, J.; Leadley, P. F.
ChemBioChem 2004, 5, 535.
Scheme 3.
10. Direct, selective functionalization at C(42)–OH is challenging due to
competitive reaction at C(31)–OH and the instability of rapamycin in the
presence of base; for examples, see: (a) Wagner, R.; Mollison, K. W.; Liu, L.;
Henry, C. L.; Rosenberg, T. A.; Bamaung, N.; Tu, N.; Wiedeman, P. E.; Or, Y.; Luly,
J. R.; Lane, B. C.; Trevillyan, J.; Chen, Y.-W.; Fey, T.; Hsieh, G.; Marsh, K.; Nuss,
M.; Jacobson, P. B.; Wilcox, D.; Carlson, R. P.; Carter, G. W.; Djuric, S. W. Bioorg.
Med. Chem. Lett. 2005, 15, 5340; (b) WO 9425071 A1 1110, 1994, American
Home Products; (c) WO 2001023395 A2 0405, 2001, American Home Products.
See also[7] and references cited therein.
butanedione monoxime ester, we observed practically no differ-
ence in acylation efficiency between the two lipases tested,
whereas the N-acetylhydroxamate ester appeared significantly
more sensitive to lipase origin. We consider the hydroxamate ester
to be an especially promising lead, as the N-acyl group can be read-
ily modified (e.g., from acetyl to halo- or trihaloacetyl, or to a chiral
acyl group, for applications in stereoselective synthesis) to adjust
acylating properties.31 Certainly both these novel acylating agents
are much more amenable to scale-up and comparatively non-
toxic32 compared with the corresponding vinyl ester and its leav-
ing group acetaldehyde.
11. (a) Degueil-Castaing, M.; De Jeso, B.; Drouillard, S.; Maillard, B. Tetrahedron Lett.
1987, 28, 953; (b) Wang, Y. F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D. E.;
Wong, C. H. J. Am. Chem. Soc. 1988, 110, 7200–7205.
12. Gu, J.; Ruppen, M. E.; Cai, P. Org. Lett. 2005, 7, 3945.
13. For a general overview of enzymatic acylations summarizing the use of active
esters and enol esters, see: Chênevert, R.; Pelchat, N.; Jacques, F. Curr. Org.
Chem. 2006, 10, 1067.
14. Acetaldehyde has been classified as a genotoxic inhalation carcinogen, see:
Gomes, R.; Meek, M. E. J. Environ. Sci. Health, C 2001, C19, 1–21.
15. (a) Britton, L. G. Process Safety Prog. 1998, 17, 138–148; (b) White, A. G.; Jones,
E. J. Soc. Chem. Ind. (London) 1950, 69, 206–209; (c) Levush, S. S.; Garbuzyuk, I.
A. Vestnik L’vovskogo Politekhnicheskogo Instituta 1988, 221, 109–110.
16. Gu, J.; Ruppen, M. E.; Raveendranath, P.; Chew, W.; Shaw, C.-C. U.S. 2005/
0234086 A1 1020, 2005.
As a conclusion, we have identified two promising alternatives
for vinyl ester-activated, sterically hindered carboxylic acids in li-
pase-catalyzed acylations. From a process point of view, both the
butanedione monooxime ester and the N-acetylhydroxamate ester
are much more desirable candidates for scale-up development and
we expect them to be useful for other applications in natural prod-
uct synthesis as well.
17. (a) Lewis, J. B.; Hedrick, G. W. J. Org. Chem. 1960, 25, 623–625; (b) Tajima, Y. JP
06135892 A 0517, 1994; Jpn. Kokai Tokkyo Koho 1994.
18. (a) Reiss, H.; Chowdhury, M. A. J. Phys. Chem. 1984, 88, 6667–6670; (b) Harmon,
M.; King, J. Oper. Res. Inc., Silver Spring, MD, USA. Avail. NTIS. U.S. NTIS, AD Rep.
1974, (AD-A017443), 142 pp. From: Gov. Rep. Announce. Index (U.S.), 1976, 76,
86.
Acknowledgments
19. The only reports we are aware of discuss the scale-up evaluation of a vinyl
ester in a continuous loop process (Roche): (a) Orsat, B.; Wirz, B.; Bischof, S.
Chimia 1999, 53, 579; (b) Bonrath, W.; Karge, R.; Netscher, T. J. Mol. Catal. B:
Enzym. 2002, 19-20, 67; Alternatively, a ketene acetal (ethoxyvinyl ester) has
been proposed as an acyl donor, but obviously suffers from some of the same
The contribution of Dr. Wayne McMahon in the preparation of 1
is acknowledged. Dr. Tom Pagano (Wyeth Pearl River Structural
Analysis Group) is thanked for NMR structure determinations. Dr.
Karen Sutherland is thanked for her encouragement.
disadvantages
(hazardous
synthesis
employing
ethoxyacetylene,
polymerization issues) and no scale-up reactions have been reported to date:
(c) Klomp, D.; Djanashvili, K.; Cianfanelli Svennum, N.; Chantapariyavat, N.;
Wong, C.-S.; Vilela, F.; Maschmeyer, T.; Peters, J. A.; Hanefeld, U. Org. Biomol.
Chem. 2005, 3, 483.
Supplementary data
Supplementary data (experimentals for acylation screen and
preparative, gram scale acylation experiments) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.08.020.
20. (a) Sheridan, R. M.; Zhang, M.; Gregory, M. A. PCT Int. Appl., WO 2006095173
A2 20060914, 2006; (b) Beckmann, C. H.; Moss, S. J.; Sheridan, R. M.; Zhang, M.;
Wilkinson, B. PCT Int. Appl., WO 2006095185 A1 20060914, 2006.
21. Isopropenyl acetate as donor in a lipase-catalyzed acylation scale-up: Bogár, K.;
Martin-Matute, B.; Bäckvall, J.-E. Beilstein J. Org. Chem. 2007, 3, No. 50.
22. Trihaloethyl esters as donors in lipase-catalyzed acylations: (a) Therisod, M.;
Klibanov, A. M. J. Am. Chem. Soc. 1986, 108, 5638–5640; (b) Wallace, J. S.; Reda,
K. B.; Williams, M. E.; Morrow, C. J. J. Org. Chem. 1990, 55, 3544; (c) Baba, N.;
Tahara, S.; Yoneda, K.; Iwasa, J. Chem. Express 1991, 6, 423–426.
References and notes
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23. Vinyl acetate, isopropenyl acetate and O-acetyl-acetonoxime all gave virtually
identical acylation results in an earlier acylation of a hindered secondary

T. Storz et al. / Tetrahedron Letters 51 (2010) 5511–5515
5515
alcohol see: Kanerva, L. T.; Sundholm, O. J. Chem. Soc., Perkin Trans. 1 1993,
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24. (a) Ghogare, A.; Sudesh Kumar, G. J. Chem. Soc. Chem. Commun. 1989, 1533; J.
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25. Tamarez, M.; Morgan, B.; Wong, G. S. K.; Tong, W.; Bennett, F.; Lovey, R.;
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339.
29. To the best of our knowledge, no reports on the use of N-acylhydroxamate
esters for enzyme-catalyzed acylation reactions have appeared in the literature
as of May 2010 (Beilstein and Scifinder on-line searches).
30. The acetamido(cyano)malonate oxime- and butanedione-(mono)oxime-
derived (4, 6) esters have not been reported in lipase-catalyzed acylations of
natural products or transfer of secondary or tertiary acyl groups before. For a
comparison of acetoneoxime, cyclopentanone oxime and benzophenone oxime
esters as acyl donors, see: (a) Salunkhe, M. M.; Nair, R. V. Enzyme Microb.
Technol. 2001, 28, 333; The butanedione(mono)oxime ester of acrylic acid has
been used in presence of a lipase to acroylate alcohol groups in polymer
precursors, see: (b) Ghogare, A.; Kumar, G. S. J. Chem. Soc., Chem. Commun.
1990, 134; (c) Athawale, V.; Manjrekar, N. Synlett 2000, 225; (d) Athawale, V.
D.; Gaonkar, S. R. Biotechnol. Lett. 1994, 16, 149; A study comparing acetone
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a lipase-
catalyzed resolution was published: (e) Mischitz, M.; Pöschl, U.; Faber, K.
Biotechnol. Lett. 1991, 13, 653; First report comparing vinyl acetate and
O-acetyl-butanedione-monooxime as acetylating agents, see: Ghogare, A.;
Sudesh Kumar, G. J. Chem. Soc., Chem. Commun 1989, 1533. After this initial
study, the butanedione(mono)oxime ester appears to have fallen into oblivion.
31. From a scale-up point of view, the higher acidity of the leaving group would be
an additional advantage of the hydroxamate versus the oxime ester, making
cosubstrate inhibition less likely (compare Faber et al., Biotechnol. Lett. 1991,
13, 653).
32. 2,3-Butanedione monoxime has been proposed as an antidote for
organophosphorus poisoning, see: (a) Sellin, L.; McArdle, J. J. Pharmacol.
Toxicol. (Oxford, UK) 1994, 74, 305; Cyano(hydroximino)ethyl acetate has also
been suggested as
a reactivator for cholinesterases inhibited by organo-
phosphorus compounds, see: (b) Cier, A.; Cuisinaud, G.; Solal, M.; Rossi, C. Bull.
Soc. Chim. Biol. 1969, 51, 753; N-Acetylhydroxamic acid (LithostatÒ) is in use as
a
human therapeutic for the treatment of kidney stone disease, see: (c)
Martelli, A.; Buli, P.; Cortecchia, V. Urology 1981, 17, 320.