Total syntheses of new proansamitocin derivatives by ring-closing metathesis

Article abstract of DOI:10.1055/s-2007-977441

The enantioselective synthesis of two new proansamitocin derivatives is described. Macrocyclization is achieved by ring-closing metathesis of appropriate alkene and diene precursors. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977441

1264
LETTER
Total Syntheses of New Proansamitocin Derivatives by Ring-Closing
Metathesis
Total
S
yntheses of
x
N
ew Proans
e
amitocin D
l
erivatives by
MRCM eyer, Andreas Kirschning*
Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffchemie (BMWZ), Leibniz Universität Hannover,
Schneiderberg 1b, 30167 Hannover, Germany
E-mail: andreas.kirschning@uni-hannover.de
Received 6 February 2007
Despite their pharmaceutical potency, the clinical devel-
opment of maytansinoids had to be stopped in phase II2a,6
due to gastrointestinal side effects and neurotoxicities.4b,7
However, efforts to develop them into clinically useful
agents is still a major issue in pharmaceutical research. So
far, knowledge of the structure–activity relationships2a,e
has not relied on total synthesis but rather on semisyn-
thetic approaches.5,8 Therefore, minimum structural
requirements for biological activity are still obscure.
Mutasynthesis9 and particularly conjugation of the ansam-
itocins to tumor-targeted antibodies for increasing phar-
maceutical selectivity are currently the most promising
strategies pursued in this field.10
Recently, we initiated a research program11,12 dedicated to
access new ansamitocins by synthetically exploiting the
3-amino-5-hydroxybenzoic acid (AHBA) block mutant of
the ansamitocin P-3 producer Actinosynnema pretiosum
(HGF073).13 As part of this project we had to prepare
proansamitocin (4), the polyketide ring-closure product,
and analogues 5 and 6 which are basically 17-membered
macrocycles missing the first propionate unit of the ketide
chain (marked in 4 in Figure 1). Mutasynthesis of these
advanced synthetic macrocycles would allow utilizing the
postketide enzymes of Actinosynnema pretiosum
(HGF073) for further functionalization (epoxidation,
N,O-methylation, side-chain esterification, carbamoyla-
tion and chlorination). In this report we disclose a total
synthesis approach toward two of these ‘mini’ proansam-
itocins 5 and 6.
Abstract: The enantioselective synthesis of two new proansamito-
cin derivatives is described. Macrocyclization is achieved by ring-
closing metathesis of appropriate alkene and diene precursors.
Key words: ansamitocins, natural product synthesis, macrolactam
antibiotics, ring-closing metathesis
Maytansine (1) was first isolated from the Ethiopian plant
Maytenus serrata1,2 and inhibits growth of different leuce-
mia cell lines as well as human solid tumors at very low
concentrations (10–3 to 10–7 g/mL). The ansamitocins P-1,
P-2, P-3 2 and P-4 3,3–5, which are of microbial origin
(Actinosynnema pretiosum), are closely related. All these
maytansinoids consist of a 19-membered macrolactam
ring and only differ in the side chain at C-3.
OR
Me
H
Cl
O
O
Me
MeO
N
1
3
H
O
7
Me
13
10
postketide enzymes
N
O
H
N,O-methylation
epoxidation
MeO
OH
Me
esterification
carbamoylation
chlorination
1: R = C(O)CH(Me)N(Me)COMe (maytansin)
2: R = C(O)CHMe2 (ansamitocin P-3)
3: R = COCH2CH(Me)2 (ansamitocin P-4)
OH
O
H
HO
Me
N
Our retrosynthetic analysis is summarized in Scheme 1.
Key issues of the planned syntheses are a ring-closing
metathesis (RCM) of 7 after intermolecular amide forma-
tion of anilines 8 and 9, respectively, with ketide fragment
10. We chose RCM for ring closure and not macrolactam-
ization because in our hands the latter reaction often had
turned out to be very problematic (low yields, double
bond migration toward the keto group).14
OH
Me
O
H
OH
R
Me
OH
N
O
Me
OMe
Me
O
4 (proansamitocin)
5, 6
OMe
Figure 1 Structures of maytansinoids maytansin (1), ansamitocins
P3 (2) and P4 (3) as well as proansamitocin (4) and ‘mini’-proansa-
mitocins 5 and 6; biosynthetic relationship between ansamitocin P3
and proansamitocin
The syntheses of the two allylated anilines 8 and 9 are de-
picted in Schemes 2 and 3, respectively. Protected AHBA
derivative 1115 was first transformed into benzyl bromide
12 which was treated with vinyl indium 1316 under Pd(0)-
catalysis to yield aniline 8 after removal of the Boc-pro-
tection.
Trimethoxybenzene 14 was transformed into arylalde-
hyde 15 using standard electrophilic substitutions
(Scheme 3). From there, benzyl bromide 16,17 which was
SYNLETT 2007, No. 8, pp 1264–1268
Advanced online publication: 18.04.2007
DOI: 10.1055/s-2007-977441; Art ID: G03307ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
5.
2
0
0
7

LETTER
Total Syntheses of New Proansamitocin Derivatives by RCM
1265
amide formation
OH
OH
O
O
H
H
Me
OH
N
Me
OH
N
R
R
Me
Me
O
O
OMe
OMe
7
5, 6
RCM
O
OPG
Me
R
HO
NH2
Me
+
OPG
MeO
O
8, 9
10
H
H
N
H
N
N
R
=
HO
MeO
OMe
MeO
6, 9
5, 8
Scheme 1 Retrosynthetic analysis
obtained after a reduction–bromination sequence, was (Yamaguchi reagent, Mukaiyama conditions, DCC–
subjected to the vinylation protocol described above. Fi- DMAP) we found that BOPCl18 acted as the best condens-
nally, the amino group was liberated by reducing the nitro ing agent yielding amide 1719 in satisfactory yield. Under
group. With both aromatic building blocks in hand, for- the conditions given in Scheme 4 b-elimination of the
mation of the amide bond was envisaged for which we TBSO group was suppressed to a minimum (<10%).
required the complex carboxylic acid 18. The scalable Ring-closing metathesis (RCM)20 using the 2nd generation
synthesis of this ketide fragment was described before by Grubbs’ catalyst afforded the macrocycle with pro-
us.11 Among several amide-forming methods tested nounced preference for the E-isomer (E/Z >10:1) which
was deprotected21 to afford ‘mini’-proansamitocin 5.22
O
BocHN
BocHN
a, b
OMe
Br
OMe
OMe
91%
OMe
OMe
CHO
a, b
c, d
OTBDPS
OTBDPS
81%
81%
O2N
11
12
OMe
OMe
14
15
69%
c, d
OMe
OMe
e
MgBr
OMe
Br
OMe
In
e, f
H2N
3
52%
13
O2N
H2N
OMe
OMe
OTBDPS
16
9
8
Scheme 3 Reagents and conditions: (a) Et2O, n-BuLi, DMF, 2 h, D
(89%); (b) HOAc, concd HNO3, 60 °C, 0.5 h (91%); (c) NaBH4, THF,
r.t., 1 h (99%); (d) PBr3, pyridine, Et2O, r.t., 0.5 h (82%); (e) 13,
formation in THF, –78 °C, 0.5 h, then r.t. and addition of Pd(dppf)Cl2,
6 h, D, (68%); (f) SnCl2·2H2O, EtOAc, D, 2.5 h (76%).
Scheme 2 Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C
to r.t., 3.5 h (98%); (b) CBr4, PPh3, CH2Cl2, r.t., 30 min (93%); (c) 13,
Pd(dppf)Cl2 (dppf: diphenylphosphinoferrocene), THF, D, 6 h (73%);
(d) TFA, CH2Cl2, r.t., 2 h (95%); (e) InCl3, THF, –78 °C, 0.5 h, then
r.t. (73%).
Synlett 2007, No. 8, 1264–1268 © Thieme Stuttgart · New York

1266
A. Meyer, A. Kirschning
LETTER
OTBS
Me
O
approach utilizes the scalable key fragment 18 and in-
cludes intermolecular amide formation using BOPCl as
condensing agent and RCM as powerful and stereoselec-
tive macrocyclization method. The synthetic sequence
presented can in principal be expanded to many new
ansamitocin derivatives and thus will help to establish the
minimum structural requirement for installing biological
activity. Work is in progress to access more maytansi-
noids by conducting feeding experiments with Actinosyn-
nema pretiosum24 and to further reveal structure-activity
relationships for these important antitumor agents.
H
TBDPSO
N
Me
a
8
OTBS
O
MeO
OTBS
O
Me
b,c
HO
17
Me
OTBS
OH
O
H
MeO
Me
OH
N
O
Me
HO
18
O
Acknowledgment
O
OMe
O
O
5
This work was supported by the Deutsche Forschungsgemeinschaft
(grant Ki 397/7-1) and by the Fonds der Chemischen Industrie. We
are grateful to M. Quitschalle for providing sufficient amounts of
building block 18. Biological tests were carried out at the Helmholtz
Center of Infectious Deseases (HZI, Braunschweig) by Dr. Florenz
Sasse.
P
N
N
BOPCl =
Cl
O
O
Scheme 4 Reagents and conditions: (a) BOPCl, 18, DIPEA,
CH2Cl2, 3 h, then addition of aniline 8, DIPEA, CH2Cl2, 18 h (78%);
(b) Grubbs’ 2nd generation cat., CH2Cl2, D, 6 h (75%); (c) HF·py,
THF, 16 h (94%).
References and Notes
(1) (a) Kupchan, S. M.; Komoda, Y.; Court, W. A.; Thomas, G.
J.; Smith, R. M.; Karim, A.; Gilmore, C. J.; Haltiwanger, R.
C.; Bryan, R. F. J. Am. Chem. Soc. 1972, 94, 1354.
(b) Kupchan, S. M.; Komoda, Y.; Branfman, A. R.; Sneden,
A. T.; Court, W. A.; Thomas, G. J.; Hintz, H. P. J.; Smith, R.
M.; Karim, A.; Howie, G. A.; Verma, A. K.; Nagao, Y.;
Dailey, R. G. Jr.; Zimmerly, V. A.; Sumner, W. C. Jr. J. Org.
Chem. 1977, 42, 2349. (c) Bryan, R. F.; Gilmore, C. J.;
Haltiwanger, R. C. J. Chem. Soc., Perkin Trans. 2 1973, 897.
(2) Also from two other plant families (Colubrina texensis,
Rhamnaceae and Trewia nudiflora, Euphorbiaceae)
maytansinoids were isolated: (a) Reider, P. J.; Roland, D.
M. Maytansinoids In The Alkaloids, Vol. 23; Brossi, A., Ed.;
Academic Press: New York, 1984, 71–156. (b) Wani, M.
C.; Taylor, H. L.; Wall, M. E. J. Chem. Soc., Chem.
Commun. 1973, 390. (c) Powell, R. G.; Weisleder, D.;
Smith, C. R. Jr.; Kozlowski, J.; Rohwedder, W. K. J. Am.
Chem. Soc. 1982, 104, 4929. (d) Powell, R. G.; Smith, C. R.
Jr.; Plattner, R. D.; Jones, B. E. J. Nat. Prod. 1983, 46, 660.
(e) Smith, C. R. Jr.; Powell, R. G. In Chemistry and
Pharmacology of Maytansinoid Alkaloids in Alkaloids, Vol.
2; Pelletier, S. W., Ed.; John Wiley and Sons: New York,
1984, 149–204.
In the same way and with similar efficiency we prepared
proansamitocin 622,23 via amide 1920(Scheme 5).
Preliminary biological tests (L929 fibroplasts from mice)
revealed no significant cytotoxic activity of macrocycles
5 and 6 (in comparison: IC50 = 0.3 ng/mL for 2) which
points to the importance of the diene, the ester side chain
and the carbamoyl group for the bioactive conformation
of ansamitocines.
In conclusion, we prepared two new 17-membered
macrocyclic derivatives of the maytansinoid proansamito-
cin. Both target compounds differed from the natural
maytansinoids in the ring size and in part in the substitu-
tion pattern of the aromatic moiety. The total synthesis
OTBS
O
H
MeO
MeO
Me
N
a
9
Me
OMe
OTBS
(3) (a) Higashide, E.; Asai, M.; Ootsu, K.; Tanida, S.; Kozai, Y.;
Hasegawa, T.; Kishi, T.; Sugino, Y.; Yoneda, M. Nature
(London) 1977, 270, 721. (b) Asai, M.; Mizuta, E.; Izawa,
M.; Haibara, K.; Kishi, T. Tetrahedron 1979, 35, 1079.
(4) A mutant of A. pretiosum spp. auranticum provided 15
additional ansamitocines: (a) Izawa, M.; Tanida, S.; Asai,
M. J. Antibiot. 1981, 34, 496. (b) Komoda, Y.; Kishi, T.
Maytansinoids, In Anticancer Agents Based on Natural
Product Models; Douros, J.; Cassady, J. M., Eds.; Academic
Press: New York, 1980, 353–389.
(5) (a) Rinehart, K. L. Jr.; Shield, L. S. Fortschr. Chem. Org.
Naturst. 1976, 33, 231. (b) Cassady, J. M.; Chan, K. K.;
Floss, H. G.; Leistner, E. Chem. Pharm. Bull. 2004, 52, 1.
(6) (a) Thigpen, J. T.; Ehrlich, C. E.; Creasman, W. T.; Curry,
S.; Blessing, J. A. Am. J. Clin. Oncol. (CCT) 1985, 6, 273.
(b) Thigpen, J. T.; Ehrlich, C. E.; Conroy, J.; Blessing, J. A.
Am. J. Clin. Oncol. (CCT) 1985, 6, 427. (c) Ravry, M. J.;
Omura, G. A.; Birch, R. Am J. Clin. Oncol. (CCT) 1985, 8,
148.
MeO
O
b, c
19
OH
O
H
Me
OH
N
Me
MeO
MeO
OMe
O
OMe
6
Scheme 5 Reagents and conditions: (a) BOPCl, 18, DIPEA,
CH2Cl2, 3 h, then addition of aniline 9, DIPEA, CH2Cl2, 18 h (63%);
(b) Grubbs’ 2nd generation cat., CH2Cl2, D, 6 h (75%); (c) HF·py,
THF, 16 h (94%).
Synlett 2007, No. 8, 1264–1268 © Thieme Stuttgart · New York

LETTER
Total Syntheses of New Proansamitocin Derivatives by RCM
OSiC(CH3)3], 0.82 [s, 9 H, OSiC(CH3)3], 0.05 (s, 3 H,
1267
(7) Issell, B. F.; Crooke, S. T. Cancer Treat. Rev. 1978, 5, 199.
(8) (a) Chari, R. V.; Martell, B. A.; Gross, J. L.; Cook, S. B.;
Shah, S. A.; Blättler, W. A.; McKenzie, S. J.; Goldmacher,
V. S. Cancer Res. 1992, 52, 127. (b) Okamoto, K.; Harada,
K.; Ikeyama, S.; Iwasa, S. Jpn. J. Cancer Res. 1992, 83,
761. (c) Liu, C.; Tadayoni, B. M.; Bourret, L. A.; Mattocks,
K. M.; Derr, S. M.; Widdison, W. C.; Kedersha, N. L.;
Ariniello, P. D.; Goldmacher, V. S.; Lambert, J. M.; Blättler,
W. A.; Chari, R. V. J. Proc. Nat. Acad. Sci. U.S.A. 1996, 93,
8618.
(9) (a) These information were basically collected from
semisynthetic work starting with the natural products as
recently described by: Widdsion, W. C.; Wilhelm, S. D.;
Cavanagh, E. E.; Whiteman, K. R.; Leece, B. A.; Kovtun,
Y.; Goldmacher, V. S.; Xie, H.; Steeves, R. M.; Lutz, R. J.;
Zhao, R.; Wang, L.; Blättler, W. A.; Chari, R. V. J. J. Med.
Chem. 2006, 49, 4392; and in references 2a and 2e.
(b) Recent review of total synthesis approaches is given in
ref. 5b.
(10) Weist, S.; Süssmuth, R. D. Appl. Microbiol. Biotechnol.
2005, 68, 141.
(11) Frenzel, T.; Brünjes, M.; Quitschalle, M.; Kirschning, A.
Org. Lett. 2006, 8, 135.
(12) Kubota, T.; Brünjes, M.; Frenzel, T.; Xu, J.; Kirschning, A.;
Floss, H. G. ChemBioChem 2006, 7, 1221.
(13) Yu, T.-W.; Bai, L.; Clade, D.; Hoffmann, D.; Toelzer, S.;
Trinh, K. Q.; Xu, J.; Moss, S. J.; Leistner, E.; Floss, H. G.
Proc. Nat. Acad. Sci. U.S.A. 2002, 99, 7968.
OSiCH3), –0.02 (s, 3 H, OSiCH3), –0.03 (s, 3 H, OSiCH3),
–0.06 (s, 3 H, OSiCH3). 13C NMR (100 MHz, CDCl3 = 77.0
ppm): d = 206.8 (s, C-9), 169.1 (s, C-1), 155.9 (s, Ar),
141.7 (s, Ar), 138.7 (s, Ar), 136.8 (d, C-2¢), 136.5 (s, C-4),
135.5 (d, Ph), 132.9 (s, Ph), 132.4 (d, C-11), 129.8 (d, Ph),
128.3 (d, C-5), 127.7 (d, Ph), 120.3 (t, C-12), 115.9 (d,
Ar), 115.8 (t, C-3¢), 112.7 (d, Ar), 108.9 (d, Ar), 88.8 (d,
C-10), 75.2 (d, C-3), 71.4 (d, C-7), 57.0 (q, 10-OCH3), 46.1
(t, C-2), 43.4 (t, C-8), 39.9 (t, C-1¢), 38.2 (d, C-6), 26.5 [q,
OSi(Ph2)C(CH3)3], 26.0 {q, OSi[(CH3)2]C(CH3)3}, 25.8 {q,
OSi[(CH3)2]C(CH3)3}, 19.5 [s, OSi(Ph2)C(CH3)3], 18.1 {s,
OSi[(CH3)2]C(CH3)3}, 18.0 {s, OSi[(CH3)2]C(CH3)3}, 16.2
(q, 6-CH3), 12.5 (q, 4-CH3), –4.5 [q, 2 × OSiC(CH3)3], –4.7
[q, OSiC(CH3)3], –5.2 [q, OSiC(CH3)3]. HRMS (ESI): m/z
[M + H]+ calcd for C52H79Si3NO6: 898.5294; found:
898.5288. 19: [a]D20 –37.5 (c = 0.8, CHCl3). 1H NMR (400
MHz, CDCl3; CHCl3 = 7.26 ppm): d = 7.97 (s, 1 H, ArH),
7.77 (s, 1 H, NH), 5.99 (ddt, J = 6.1, 10.3, 16.7 Hz, 1 H, 2¢-
H), 5.68 (ddd, J = 6.9, 10.3, 17.2 Hz, 1 H, 11-H), 5.45 (ddd,
J = 1.3, 1.3, 17.2 Hz, 1 H, 12-H), 5.40–5.43 (m, 1 H, 5-H),
5.38 (ddd, J = 1.3, 1.3, 10.3 Hz, 1 H, 12-H¢), 5.00 (ddd, J =
1.6, 3.3, 10.3 Hz, 1 H, 3¢-H), 4.89 (dd, J = 1.6, 3.3, 16.7 Hz,
1 H, 3¢-H¢), 4.51 (dd, J = 3.8, 8.2 Hz, 1 H, 3-H), 4.07 (dt, J =
5.0, 6.6 Hz, 1 H, 7-H), 4.05 (ddd, J = 1.3, 1.3, 6.9 Hz, 1 H,
10-H), 3.83 (s, 3 H, ArOCH3), 3.78 (s, 3 H, ArOCH3), 3.69
(s, 3 H, ArOCH3), 3.42 (dd, J = 1.4, 6.0 Hz, 2 H, 1¢-H, 1¢-H¢),
3.34 (s, 3 H, 10-OCH3), 2.69 (dd, J = 6.6, 17.1 Hz, 1 H, 8-
H), 2.60 (dd, J = 4.8, 17.1 Hz, 1 H, 8-H¢), 2.50 (m, 1 H, 6-
H), 2.51 (dd, J = 3.8, 13.7 Hz, 1 H, 2-H), 2.44 (dd, J = 8.2,
13.7 Hz, 1 H, 2-H¢), 1.65 (d, J = 1.0 Hz, 3 H, 4-CH3), 0.85
(d, J = 4.4 Hz, 3 H, 6-CH3), 0.84 [s, 9 H, OSiC(CH3)3], 0.83
[s, 9 H, OSiC(CH3)3], 0.05 (s, 3 H, OSiCH3), 0.02 (s, 3 H,
OSiCH3), 0.01 (s, 3 H, OSiCH3), –0.03 (s, 3 H, OSiCH3). 13C
NMR (100 MHz, CDCl3 = 77.0 ppm): d = 206.8 (s, C-9),
169.1 (s, C-1), 149.1 (s, Ar), 143.3 (s, Ar), 140.8 (s, Ar),
137.1 (s, C-2¢), 136.4 (s, C-4), 132.4 (d, C-11), 128.4 (d, C-
5), 127.4 (s, Ar), 126.4 (s, Ar), 120.3 (t, C-12), 115.0 (t, C-
3¢), 103.4 (d, Ar), 88.9 (d, C-10), 75.4 (d, C-3), 71.4 (d, C-
7), 61.5 (q, ArOCH3), 60.9 (q, ArOCH3), 56.9 (q, 10-OCH3),
55.9 (q, ArOCH3), 46.5 (t, C-2), 43.4 (t, C-8), 38.1 (d, C-6),
28.7 (t, C-1¢), 25.9 {q, OSi[(CH3)2]C(CH3)3}, 25.8 {q,
OSi[(CH3)2]C(CH3)3}, 18.1 {s, OSi[(CH3)2]C(CH3)3}, 18.0
{s, OSi[(CH3)2]C(CH3)3}, 16.0 (q, 6-CH3), 12.4 (q, 4-CH3),
–4.5 [q, 2 × OSiC(CH3)3], –4.6 [q, OSiC(CH3)3], –5.2 [q,
OSiC(CH3)3]. HRMS (ESI): m/z [M + Na]+ calcd for
C39H67Si2NO8: 756.4303; found: 756.4306.
(14) Kashin, D.; Meyer, A.; Wittenberg, R.; Schöning, K.-U.;
Gommlich, S.; Kirschning, A. Synthesis 2007, 304.
(15) Becker, A. M.; Rickards, R. W.; Brown, R. F. C.
Tetrahedron 1983, 39, 4189.
(16) Other vinylmetal species such as vinylstannane and
vinylzinc only gave reduced yields of the coupling product
in Pd(0)-catalyzed cross-coupling reactions: Pérez, I.; Pérez
Sestelo, J.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123,
4155.
(17) Andrus, M. B.; Meredith, E. L.; Soma Sekhar, B. B. V. Org.
Lett. 2001, 6, 259.
(18) Cabré, J.; Palomo, A. L. Synthesis 1984, 413.
(19) General Procedure for the Preparation of Amides 17 and
19: Ketoacid 18 (1 equiv) was dissolved in CH2Cl2, then
treated with BOPCl (1 equiv) and DIPEA (1 equiv) and
stirred at r.t. for 3 h. A solution of aniline 8/9 (1 equiv) and
DIPEA (1 equiv) in CH2Cl2 was added over a period of 2 h.
After completion (ca. 18 h), the reaction was terminated by
addition of aq phosphate buffer (pH 7) and CH2Cl2. The
organic phases were combined, dried over Na2SO4 and the
solvent was removed under reduced pressure. Flash column
chromatography over silica eluting with hexanes–EtOAc
(20:1) furnished the corresponding amide 17/19.
(20) (a) Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed.
2006, 45, 6086; Angew. Chem. 2006, 118, 6232.
(b) Lemarchand, A.; Bach, T. Synthesis 2005, 1977.
(c) McErlean, C. S. P.; Proisy, N.; Davis, C. J.; Boland, N.
A.; Sharp, S. Y.; Boxall, K.; Slawin, A. M. Z.; Workman, P.;
Moody, C. J. Org. Biomol. Chem. 2007, 5, 531.
Spectroscopic data for 17: [a]D20 –59.0 (c = 1.2, CHCl3). 1H
NMR (400 MHz, CDCl3; CHCl3 = 7.26 ppm): d = 7.69–7.71
(m, 4 H, OTBDPS), 7.50 (s, 1 H, NH), 7.33–7.43 (m, 6 H,
OTBDPS), 6.95 (s, 1 H, ArH), 6.83 (s, 1 H, ArH), 6.27 (s, 1
H, ArH), 5.73 (ddt, J = 6.7, 10.2, 16.9 Hz, 1 H, 2¢-H), 5.67
(ddd, J = 6.9, 10.3, 17.2 Hz, 1 H, 11-H), 5.44 (ddd, J = 1.3,
1.3, 17.2 Hz, 1 H, 12-H), 5.37 (ddd, J = 1.3, 1.3, 10.3 Hz, 1
H, 12-H¢), 5.33–5.37 (m, 1 H, 5-H), 4.92 (ddd, J = 1.6, 1.6,
17.1 Hz, 1 H, 3¢-H), 4.89 (ddd, J = 1.6, 1.6, 17.1 Hz, 1 H, 3¢-
H¢), 4.39 (dd, J = 3.5, 7.3 Hz, 1 H, 3-H), 4.01–4.06 (m, 2 H,
7-H, 10-H), 3.33 (s, 3 H, 10-OCH3), 3.13 (s, 1 H, 1¢-H), 3.12
(s 1 H, 1¢-H¢), 2.66 (dd, J = 6.7, 17.2 Hz, 1 H, 8-H), 2.57 (dd,
J = 4.6, 17.2 Hz, 1 H, 8-H¢), 2.47–2.52 (m, 1 H, 6-H), 2.42
(dd, J = 3.8, 13.8 Hz, 1 H, 2-H), 2.36 (dd, J = 7.8, 13.8 Hz,
1 H, 2-H¢), 1.59 (d, J = 1.6 Hz, 3 H, 4-CH3), 1.08 (s, 9 H,
OTBDPS), 0.86 (d, J = 7.0 Hz, 3 H, 6-CH3), 0.84 [s, 9 H,
(21) Tetra-n-butylammonium fluoride (TBAF) turned out to be
too basic for inducing the elimination of the siloxy group at
C-3.
(22) General Procedure for the Preparation of Macrocycles 5
and 6: Amide 17/19 (1 equiv) was dissolved in anhyd
CH2Cl2, treated with Grubbs’ 2nd generation catalyst (0.2
equiv) and heated to reflux. After completion (ca. 6 h), the
reaction was terminated by the addition of aq phosphate
buffer (pH 7). The organic phases were combined, dried over
Na2SO4 and the solvent was removed under reduced
pressure. Flash column chromatography over silica with
hexanes–EtOAc (20:1) as eluent yielded the corresponding
protected macrolactams which were dissolved in anhyd THF
and treated with HF·Py (ca. 70% HF, excess) at r.t. After
Synlett 2007, No. 8, 1264–1268 © Thieme Stuttgart · New York

1268
A. Meyer, A. Kirschning
LETTER
completion (ca. 16 h), the reaction mixture was neutralized
with a sat. NaHCO3 solution. The aqueous phase was
extracted with EtOAc, the organic phases were combined,
dried over Na2SO4 and the solvent was removed under
reduced pressure. Flash column chromatography over silica
with CH2Cl2–MeOH (50:1) as eluent yielded the
Hz, 1 H, 2-H), 2.77 (dd, J = 3.1, 16.7 Hz, 1 H, 2-H¢), 2.54
(dd, J = 1.6, 16.9 Hz, 1 H, 8-H), 2.29 (dd, J = 10.5, 16.9, 10.5
Hz, 1 H, 8-H¢), 2.31 (m, 1 H, 6-H), 1.62 (s, 3 H, 4-CH3), 1.01
(d, J = 6.3 Hz, 3 H, 6-CH3). 13C NMR (100 MHz, CD3OD =
49.0 ppm): d = 208.2 (s, C-9), 171.8 (s, C-1), 150.5 (s, Ar),
143.9 (s, Ar), 142.7 (s, Ar), 136.8 (s, Ar), 134.3 (d, C-12),
129.5 (s, C-4), 127.4 (d, C-5), 127.3 (s, Ar), 125.0 (d, C-11),
104.5 (d, Ar), 88.7 (d, C-10), 72.9 (d, C-7), 70.7 (d, C-3),
61.7 (q, ArOCH3), 61.4 (q, ArOCH3), 57.3 (q, 10-CH3), 56.4
(q, ArOCH3), 44.9 (t, C-2), 42.6 (t, C-8), 39.4 (d, C-6), 27.9
(t, C-13), 18.1 (q, 6-CH3), 14.4 (q, 4-CH3). HRMS (ESI):
m/z [M + Na+] calcd for C25H35NO8: 500.2260; found:
500.2260.
corresponding macrolactam 5/6.
Spectroscopic data for 5: [a]D20 –134.6 (c = 1.0, MeOH). 1H
NMR (400 MHz, CD3OD; CH3OH = 3.31 ppm): d = 7.90 (s,
1 H, NH), 7.10 (dd, J = 1.6, 1.6 Hz, 1 H, ArH), 6.51 (dd, J =
2.1, 2.1 Hz, 1 H, ArH), 6.39 (dd, J = 1.6, 2.1 Hz, 1 H, ArH),
6.06 (dddd, J = 0.9, 6.7, 8.0, 15.5 Hz, 1 H, 12-H), 5.41 (psd,
J = 9.3 Hz, 1 H, 5-H), 5.26 (ddt, J = 1.1, 8.1, 15.5 Hz, 1 H,
11-H), 4.31–4.37 (m, 2 H, 3-H, 10-H), 3.96 (ddd, J = 3.6,
8.5, 8.5 Hz, 1 H, 7-H), 3.32–3.35 (m, 2 H, 13-H, 13-H¢), 3.33
(s, 3 H, 10-OCH3), 2.75 (dd, J = 3.6, 13.7 Hz, 1 H, 2-H), 2.62
(dd, J = 6.6, 13.7 Hz, 1 H, 2-H), 2.50–2.54 (m, 2 H, 8-H, 8-
H¢), 2.44–2.49 (m, 1 H, 6-H), 1.66 (d, J = 0.9 Hz, 3 H, 4-
CH3), 0.96 (d, J = 6.3 Hz, 3 H, 6-CH3). 13C NMR (100 MHz,
CD3OD = 49.0 ppm): d = 209.2 (s, C-9), 171.5 (s, C-1),
158.9 (s, Ar), 142.5 (s, Ar), 140.4 (s, Ar), 138.7 (s, C-4),
137.9 (d, C-12), 127.0 (d, C-5), 126.7 (d, C-11), 113.1 (d,
Ar), 112.9 (d, Ar), 105.7 (d, Ar), 89.9 (d, C-10), 74.3 (d, C-
7), 73.0 (d, C-3), 57.0 (q, 10-OCH3), 44.7 (t, C-8), 42.6 (t, C-
2), 40.0 (d, C-6), 39.3 (t, C-13), 17.7 (q, 6-CH3), 14.7 (q, 4-
CH3). HRMS (ESI): m/z [M – H+] calcd for C22H29NO6:
402.1917; found: 402.1923.
(23) We tested oxidation [(NH4)2Ce(NO3), MeCN] of the
aromatic moiety present in the silyl-protected precursor of 6
but could only isolate the ortho-quinone 20 (Figure 2 in 71%
yield instead of the para-quinone present in geldanamycin.
See also: (a) Andrus, M. B.; Meredith, E. L.; Hicken, E. J.;
Simmons, B. L.; Glancey, R. R.; Ma, W. J. Org. Chem.
2003, 68, 8162. (b) Lemarchand, A.; Bach, T. Tetrahedron
2004, 60, 9659.
OTBS
O
H
Me
N
Me
O
OMe
OTBS
6: 1H NMR (400 MHz, CD3OD; CH3OH = 3.31 ppm): d =
8.01 (t, J = 1.51 Hz, 1 H, ArH), 5.92 (dddd, J = 0.6, 3.4, 7.9,
15.5 Hz, 1 H, 12-H), 5.58 (psd, J = 8.5 Hz, 1 H, 5-H), 5.26
(dd, J = 7.0, 15.5 Hz, 1 H, 11-H), 4.40 (m, 1 H, 3-H), 4.21
(d, J = 7.0 Hz, 1 H, 10-H), 3.93 (ddd, J = 1.6, 8.9, 10.5 Hz,
1 H, 7-H), 3.82 (s, 3 H, ArOCH3), 3.70–3.81 (m, 1 H, 13-H),
3.75 (s, 3 H, ArOCH3), 3.68 (s, 3 H, ArOCH3), 3.33 (s, 3 H,
10-OCH3), 3.13–3.26 (m, 1 H, 13-H¢), 2.92 (dd, J = 4.5, 16.7
O
O
OMe
20
Figure 2
(24) Meyer, A.; Brünjes, M.; Taft, F.; Frenzel, F.; Sasse, F.;
Kirschning, A.; unpublished results.
Synlett 2007, No. 8, 1264–1268 © Thieme Stuttgart · New York

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