Chiral crotylsilane-based approach to benzoquinoid ansamycins: Total synthesis of (+)-macbecin I

Article abstract of DOI:10.1021/ja974318b

A highly convergent total synthesis of the antitumor antibiotic (+)- macbecin I (1) has been achieved through the homologation of the aldehyde 3 (C5-C21 aromatic fragment) to the E, Z-dienoate 2 by employing a sequential olefination strategy. Subsequent m

Full text of DOI:10.1021/ja974318b

J. Am. Chem. Soc. 1998, 120, 4113-4122
4113
Chiral Crotylsilane-Based Approach to Benzoquinoid Ansamycins:
Total Synthesis of (+)-Macbecin I
James S. Panek,* Feng Xu, and Ana C. Rondo´n
Contribution from the Department of Chemistry, Metcalf Center for Science and Engineering, Boston
UniVersity, Boston, Massachusetts 02215
ReceiVed December 19, 1997
Abstract: A highly convergent total synthesis of the antitumor antibiotic (+)-macbecin I (1) has been achieved
through the homologation of the aldehyde 3 (C5-C21 aromatic fragment) to the E,Z-dienoate 2 by employing
a sequential olefination strategy. Subsequent macrolactonization and a final two-step oxidation sequence were
the principle steps used to complete the synthesis. Six of the seven syn-stereochemical relationships (C6-C7,
C10-C11, and C14-C15) were introduced using our asymmetric crotylation bond construction methodology.
The C12 stereocenter was introduced by an alkoxy-directed hydroboration reaction. An alternative strategy
for introducing the C10 stereo center via a diastereoselective hydroboration reaction of 1,1-disubstituted olefin
6b provided a more atom efficient approach to intermediate 7.
Introduction
(+)-Macbecin I (1) is a member of the class of biologically
active ansamycin antibiotics (Figure 1). Structurally, these
natural products can be divided into two broad classes,
naphthalenic ansamycins and benzenic ansamycins.1 The
naphthalenic ansamycins also include the rifamycins, strepto-
varicins, tolypomycin, and naphthomycin; the benzenic ansa-
mycins include maytansine, geldanamycin, colubrinol, herbi-
mycin, and macbecin (Figure 2). The well-known maytansines
were once advocated as promising antitumor agents, and
rifamycin is used clinically as an antitubercular and antibacterial
drug.2
Figure 1. (+)-Macbecin I (1).
Macbecin I (1) and its hydroquinone analogue macbecin II
were isolated in 1980.3 The structures and absolute stereo-
chemistry of these natural products were determined by X-ray
crystallography.4 A stereoview of a minimized conformation
of (+)-macbecin I illustrates its topological characteristics
(Figure 3). An X-ray structure was also obtained for herbimycin
A,5 and the absolute configurational assignment was confirmed
by total synthesis.6 The stereochemistry of geldanamycin has
not yet been published, although circumstantial evidence sug-
gests that there is a common biosynthetic pathway, and hence
is analogous to those of herbimycin A and macbecin I. The
antibiotics possess a 19-membered ring lactam in which the ansa
(1) (a) Lu¨ttringhau¨s, A.; Gralheer, H. Justus Liebigs Ann. Chem. 1942,
67, 550-552. (b) Prelog, V.; Oppolzer, W. HelV. Chim. Acta 1973, 56,
2279-2285.
(2) (a) Burfani, M.; Kluepfel, D.; Lancini, G.; Leitish, J.; Mesentser, A.
S.; Prelog, V.; Schook, F. P.; Sensi, P. HelV. Chim. Acta 1973, 56, 2315-
2318. (b) White, R. J.; Martinelli, E.; Gallo, G. G.; Lancini, G. Nature
1973, 243, 273-275. (c) Karlsson, A.; Sartori, G.; White, R. J. Eur. J.
Biochem. 1974, 47, 251-253. (d) Johnson, R. D.; Haber, A.; Rinehart, K.
L. J. Am. Chem. Soc. 1974, 96, 3316-3318. (f) Haber, A.; Johnson, R. D.;
Rinehart, K. L.; J. Am. Chem. Soc. 1977, 99, 3541-3342.
(3) (a) Yamakim, H.; Iguchi-Ariga, S.; Ariga, H. J. Antibiot. 1989, 42,
604-610. (b) Tanida, S.; Hasegawa, T.; Higashide, E. J. Antibiot. 1980,
33, 199-204.
Figure 2. Representative structures of related ansamycins.
chain is linked to a substituted benzoquinone ring at the meta
position. The complex ansa chain contains seven stereogenic
centers, an isolated trisubstituted double bond, and a (Z,E)-diene
(Figure 1).
The biological activities and the structural complexity ex-
hibited by the benzoquinoid ansamycins make them attractive
molecules for synthesis. Over the past few years, two total
syntheses of (+)-macbecin I (1) have been reported by Baker7
(4) Muroi, M.; Haibara, K.; Asai, M.; Kamiya, K.; Kishi, T. Tetrahedron
1981, 37, 1123-1130.
(5) Furusaki, A.; Matsumoto, T.; Nakagawa, A.; Omura, S. J. Antibiot.
1980, 33, 781-785.
(6) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.; Tamai, T.; Tatsuta,
K. Tetrahedron Lett. 1991, 32, 6015-6018.
(7) (a) Baker, R.; Castro, J. J. Chem. Soc., Chem. Commun. 1989, 378-
381. (b) Baker, R.; Castro, J. J. Chem. Soc., Perkin Trans. 1 1990, 47-65.
S0002-7863(97)04318-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/17/1998

4114 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Panek et al.
Scheme 1
Figure 3. (+)-Macbecin I 3-D view (calculated with Chem3D Pro
using MM2 minimization techniques).
and Evans8 and formal syntheses have been reported by Martin9
and Kallmerten.10 Our first approach to the total synthesis of
1 was published in 1995.11
Synthetic Analysis
It was our intention to design a pathway that could address
the stereoselective installation of the stereogenic centers utilizing
our chiral (E)-crotylsilane methodology. The use of these silane
reagents bearing C-centered chirality represents a fundamentally
different approach from chiral enolate based bond construction
commonly used in the preparation of stereochemically complex
molecules. A retrosynthetic analysis of 1 suggested that a first
disconnection at the amide bond would provide an acyclic
precursor seco acid 2 (Scheme 1). The macrolactonization of
such an intermediate is well-precedented in the syntheses of
benzenoid ansamycins maytansine and (-)-N-methylmay-
tansine,12 as well as in the previous two syntheses of (+)-
macbecin I.7,8 Further disconnection of the diene moiety
resulted in the advanced intermediate 3, which contains all seven
resident stereogenic centers of the target. The C6-C7 syn
relationship of the hydroxy and methyl groups was established
by addition of chiral crotylsilane 9c to advanced R,â-unsaturated
aldehyde 4 under Lewis acid-catalyzed conditions. Disconnec-
tion at the double bond simplified the structure to intermediate
5 that was synthesized using two distinct approaches. The first
route involved the 1,2-diol cleavage of intermediate 7 and
addition of crotylsilane 9b to the resulting aldehyde 6a.11 The
second approach relied on a diastereoselective hydroboration
of the allylic alcohol 6b, which was also derived from diol 7,
introducing the syn relationship between C10 and C11. Inter-
mediate 7 was prepared from adduct 8, which was obtained
through a Lewis acid-promoted diastereoselective addition
reaction between chiral crotylsilane 9a and dimethyl acetal 10,
followed by a heteroatom-directed hydroboration (Figure 4).13
semblage of the C11-C21 aromatic fragment which relied on
our chiral crotylsilane bond construction methodology.14 The
Lewis acid-promoted addition 9a to dimethyl aryl acetal 10
allowed the assemblage of a highly functionalized intermediate
8, which included three stereogenic centers of the original target
molecule. Our design thoughts in this area were as follows:
the 2,5-dimethoxy-5-nitro core of this intermediate should be
easily converted into the aminobenzoquinone moiety of the
natural product after macrolactonization. The R-benzyloxy ester
functionality facilitates the alkoxy-directed hydroboration reac-
tion to introduce the C12 stereocenter with high stereoselectivity
(vide infra).13 This benzyloxy substituent not only played a
crucial role during the installation of C12 but also was necessary
to access intermediate 7, allowing the successful introduction
of C10 (vide infra). The synthesis of 8 was initiated by
construction of the dimethoxy aryl acetal 10, which is derived
from p-methoxyphenol.15 The desired 2,5-dimethoxy-3-ni-
trobenzyl dimethyl acetal 10 was obtained as a yellow oil in
four steps and in 52% overall yield. In accordance with our
previous reports,16 combining acetal 10 and chiral crotylsilane
9a in CH2Cl2, in the presence of a catalytic amount of TMSOTf
(0.5 equiv) at -78 °C for 16 h, afforded the desired adduct 8
as a single diastereomer (>30:1 syn/anti) in 89% yield.
Results and Discussion
Construction of C11-C21 Aromatic Fragment. The
synthesis of (+)-macbecin I (1) was initiated with the as-
(8) (a) Evans, D. A.; Miller, S. J.; Ennis, M. D.; Ornstein, P. L. J. Org.
Chem. 1992, 57, 1067-1069. (b) Evans, D. A.; Miller, S. J.; Ennis, M. D.
J. Org. Chem. 1993, 58, 471-485.
(9) Martin, S. F.; Dodge, J. A.; Burgess, L. E.; Hartmann, M. J. Org.
Chem. 1992, 57, 1070-1072.
Introduction of the C12 Stereocenter. At this point, we
were faced with the task of devising a regio- and stereoselective
oxygenation reaction of the isolated trans double bond of the
(10) Kallmerten, J.; Eshelman, J. E.; Epps, J. L. Tetrahedron Lett. 1993,
34, 749-752.
(11) Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117, 10587-10588.
(12) (a) Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Cho, C.; Hua,
D. H. J. Am. Chem. Soc. 1980, 102, 6612-6615. (b) Corey, E. J.; Weihel,
L. O.; Chamberlin, A. R.; Lipshutz, B. J. Am. Chem. Soc. 1980, 102, 1439-
1441.
(14) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316.
(15) Rubenstein, L. J. Chem. Soc. 1925, 127, 1998-2004.
(16) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790-
5792.
(13) Panek, J. S.; Xu, F. J. Org. Chem. 1992, 57, 5288-5290.

Total Synthesis of (+)-Macbecin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4115
Scheme 4
Figure 4. Required stereoselective oxygenation of 8.
Scheme 2
Scheme 5
under mild conditions (2,6-di-tert-butylpyridine, MeOTf, CH2-
Cl2, rt), afforded intermediate 13 in approximately 80% overall
yield (Scheme 4). When a stronger base (NaH) was employed
to generate the C12 alkoxide in the methylation, an SN-Ar-type
(IPSO) intramolecular substitution at the o-methoxy group by
the alkoxide led to formation of a cyclic aryl ether.18
Scheme 3
At this stage, four of the seven stereocenters (C11, C12, C14,
and C15) have been assembled in only two steps (asymmetric
crotylation and heteroatom-directed hydroboration) with two
subsequent steps for primary alcohol protection and methyl ether
formation. With intermediate 13 in hand, introduction of C10
stereogenic center was pursued.
Installation of the C10 Stereogenic Center. A closer
examination of adduct 5, revealed that the C10-C11 bond could
be constructed by a double stereodifferentiating aldol condensa-
tion or perhaps a crotylation reaction. This was especially
suitable for an in situ-generated oxocarbenium addition between
crotylsilane 9b and aldehyde 6a. By employing this three-
component reaction system, we can establish a syn relationship
between the methoxy and the methyl groups in a single step
with high levels of diastereoselection. The strategy began with
the cleavage of the primary silyl ether 13 to afford the
intermediate alcohol 14 in quantitative yield (Scheme 5).
The crucial debenzylation was first carried out with BCl3 (1.5
equiv) in CH2Cl2 at -78 °C. It is important to note that with
more equivalents of BCl3 or a higher reaction temperature, the
aromatic fragment was also cleaved from the main acyclic chain.
However, if the same transformation was performed with
BCl3‚SMe2 (2.0 equiv) in CH2Cl2 from -78 to 0 °C, the desired
1,2-diol was obtained in 95% isolated yield. The 1,2-diol bond
cleavage was accomplished by NaIO4 and NaHCO3 in acetone/
H2O at room temperature to provide aldehyde 6a in 80% yield
(three steps from 13). After obtaining the R-methoxy aldehyde
6a, we then addressed the critical double-stereodifferentiating
crotylation reaction for the introduction of the C10/C11 stereo-
centers. Aldehyde 6a was combined with TMSOMe and
crotylsilane 9b in CH2Cl2 and subsequently treated with
TMSOTf (2 equiv) from -78 to -50 °C for 48 h. This three-
component reaction system afforded the desired crotylation
C11-C15 aromatic subunit 8. Figure 3 illustrates the required
transformation, given the fact that we had an efficient route to
install three of the seven stereocenters in compound 8 through
the use of asymmetric crotylation chemistry.
We envisioned the possibility of oxygenating the E double
bond of the R-alkoxy-â,γ-unsaturated methyl ester 8 by a borane
methyl sulfide hydroboration reaction. Gratifyingly, we en-
countered what seemed to be an intramolecular process, wherein
the directing alkoxy group is produced from a selective
borohydride reduction of the methyl ester, resulting in good
levels of regio- and diastereoselection (Scheme 3).13 Methyl
ester 8 was treated with BH3‚SMe2 (1.05 equiv) in THF at 0
°C for 2 h, before it was allowed to warm to room temperature
(rt) for 16 h. The reaction mixture was then oxidized by alkaline
hydrogen peroxide (4-5 equiv) at 0 °C. The desired 1,3-diol
11 was obtained with 8.5-11:1 anti/syn (C11/C12) diastereo-
selection in 85% isolated yield. The stereochemical course of
this reaction is consistent with an intramolecular mechanism
and suggests that the R-alkoxy group adjacent to the carbonyl
plays a crucial role in this process. It appears to be responsible
for polarizing the adjacent double bond, thereby reinforcing the
positional and olefin face selectivity of the hydroboration
pathway. It also enhances the rate of carbonyl reduction, so
that it competes favorably with the intermolecular olefin
hydroboration pathway, achieving the selective formation of the
boronate-like intermediate.13,17
(17) The selective reduction of R-hydroxy esters with BH3‚SMe2 in
combination with NaBH4 has been reported. See: (a) Saito, S.; Hasegawa,
T.; Inaba, M.; Nishida, R.; Fuji, T.; Nomizu, S.; Moriwake, T. Chem. Lett.
1984, 1389-1392. (b) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.;
Moriwake, T. Tetrahedron 1992, 48, 4067-4086.
(18) Spectral data are consistent with the following structure:
Selective protection of the primary alcohol of 11 using TBSCl
(1.05 equiv) and imidazole (4-5 equiv) in anhydrous DMF/
Et2O at 0 °C, followed by methylation of the secondary alcohol

4116 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Panek et al.
Scheme 6
adduct 15 in 80% isolated yield, with a diastereoselection of
12:1 favoring the syn homoallylic ether (Scheme 6). This syn
bond construction reinstalled the C11 stereocenter and intro-
duced the C10 methyl group. Unfortunately, the reaction did
not go to completion when the temperature was maintained
below -50 °C or when less than 2 equiv of TMSOTf was used
to promote the reaction. The lower reactivity and diastereose-
lection of this process may result from a mismatched transition
state between chiral aldehyde 6a and chiral silane reagent 9b,
with the C11-C12 stereocenters emerging with an anti-Felkin
stereochemical relationship, as the crotylation is illustrated with
the antiperiplanar transition state (Scheme 6).19 Although the
selectivity of this reaction did not reach the levels obtained in
the acetal additions previously described, the chiral silane
reagent is still capable of overriding the chirality of aldehyde
6a, determining the stereochemistry of this double-stereodif-
ferentiating reaction.
Figure 5. Comparison of Rh(I)-catalyzed and uncatalyzed hydrobo-
ration.
Scheme 7
Scheme 8
The C8/C9 trisubstituted double bond was elaborated through
ozonolysis of olefin 15 to obtain aldehyde 5, which was also
synthesized by means of an uncatalyzed hydroboration of the
terminal allylic alcohol 6b (vide infra). Even though C10 was
successfully installed using a crotylation reaction, a more atom
economical approach that would preserve the C11 stereocenter
installed in the first addition of aryl acetal 10 and crotylsilane
9a, giving us an alternative route with higher efficiency, was
then undertaken. In 1992, Evans and co-workers20 reported that
1,1-disubstituted olefins can be converted to terminal alcohols
with high levels of syn diastereoselection between the newly
formed stereocenter C2 and a preexisting C3 stereocenter by
using catechol borane and RhCl(Ph3P)3 (Wilkinson’s catalyst).
This catalyzed hydroboration provided the complimentary
stereochemistry of the uncatalyzed hydroboration of 1,1-
disubstituted olefins using bulky dialkylboranes (Figure 5).
Although the mechanism of the stereochemical-determining step
of this reaction is not fully understood,20 a sufficient number
of examples were documented to make this a viable option.
However, treatment of the intermediate 19 with RhCl(Ph3P)3
and freshly distilled catechol borane in THF at room temperature
for 16 h followed by neutral oxidation with H2O2 and KH2-
PO4-NaOH buffer (pH ) 7) afforded a mixture of 6:1 primary
alcohols in 66% yield. Unfortunately, this transformation
favored the formation of the incorrect C10 isomer, which was
appeared to be a feasible approach based on a similar transfor-
mation reported by Tatsuta6 and co-workers in the total synthesis
of herbimycin A (Scheme 7). Similar findings were also
reported by Paterson and Channon.21
The synthesis of the 1,1-disubstituted olefin intermediate 19
was initiated by a Swern oxidation of 14, which afforded the
R-benzyloxy aldehyde 16 in 93% yield (Scheme 8). Treating
aldehyde 16 with Me3Al in CH2Cl2 at -78 °C for 15 min
afforded the desired secondary alcohol 17 in 92% yield with
good levels of diastereoselection (>12:1).22 The final construc-
tion of the intermediate terminal olefin 19 from 17 was
accomplished by a stepwise Swern oxidation and Wittig
homologation (LHMDS, Ph3PCH3Br, Et2O, -78 °C to rt)
sequence in 63% overall yield. The solvent employed had a
significant impact on the outcome of the Wittig reaction. When
THF was used as the solvent, a dramatic drop in the yield
(∼40%) of the reaction was observed.
1
confirmed by analysis of the H NMR of the corresponding
(21) Paterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33, 797-800.
(22) Nucleophilic additions to aldehyde 16 under alkaline conditions
(CH3MgBr, MeLi, (CH3)2CuLi) did not provide useful yields of desired
alcohol. When CH3MgBr was used in the reaction at -100 °C in Et2O or
THF, no desired product could be isolated and the starting aldehyde had
decomposed extensively. The cuprate reagent gave low yields (∼20%) in
Et2O, while the MeLi provided a mixture (∼3:1) of desired secondary
alcohols in about 40-50% yield in Et2O and 20-30% yield in THF at
-100 °C. The poor results from these reactions may be due to the electron-
withdrawing effect of the aromatic nitro group, as it is capable of activating
the adjacent methyl group to nucleophilic substitution. Methyl nucleophiles,
therefore, attack the aromatic methyl, resulting in demethylation of the
benzenic ring.
acetonides.
As an alternative route to install C10/C11 using the proposed
hydroboration of the 1,1-disubstituted terminal olefin, treatment
of allylic alcohol 6b under uncatalyzed hydroboration conditions
(19) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1-76.
(20) (a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc.
1992, 114, 6671-6679. (b) Evans, D. A.; Fu, G. C.; Anderson, B. A. J.
Am. Chem. Soc. 1992, 114, 6679-6685. (c) Burgess, K.; Donk, W. A.;
Westcott, S. A.; Marder, T. B.; Baker, R. T.; Calabrese, J. C. J. Am. Chem.
Soc. 1992, 114, 9350-9359.

Total Synthesis of (+)-Macbecin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4117
Scheme 9
Scheme 10
Hydroboration of olefin 19 with BH3‚THF in THF afforded
a mixture of primary alcohols in a 1.5:1 diastereomeric ratio
favoring the syn isomer (desired product). Alkylboranes
(catechol borane, 9-BBN, or (+)-IPC2BH) all favored formation
of the anti product. The chiral borane reagents had no
significant effect on the diastereomeric outcome of this reaction.
Attempts to remove the benzyl group from intermediate 19
and perform the hydroboration with the free hydroxy group
failed to provide the required alcohol 6b. Deprotection attempts
with TiCl4, BCl3, BBr3, BCl3‚SMe2, and lithium naphthalenide
were among the different conditions that were surveyed. A
more labile protecting group was then necessary. Taking into
account that the benzyloxy group was a crucial unit for the
heteroatom-directed hydroboration, the new protective group
had to be introduced at a later stage. A silicon-based protecting
group strategy at C10 was envisioned to be sufficiently stable
to the reaction sequence yet easily removed under acidic
conditions to achieve intermediate 6b. Therefore, a TBS-
protected ether was introduced at the 1,2-diol 7. Protection of
both hydroxyl groups using TBSCl (2.5 equiv) and imidazole
(6 equiv) in DMF at 0 °C, followed by selective deprotection
of the primary TBS ether under HF‚pyridine conditions, afforded
the corresponding alcohol 21 in excellent yield (89%, two steps).
Following the same synthetic sequence as described in Scheme
8, to construct the terminal double bond, the desired intermediate
25 was obtained in six steps 64% overall yield. Removal of
the silyl protecting group using 48% aqueous HF in CH3CN at
room temperature proceeded in quantitative yield, affording pure
allylic alcohol 6b (Scheme 9).
Hydroboration of terminal allylic alcohol 6b gave low
selectivities when BH3‚SMe2 was used as the hydroborating
agent. However, in the presence of BH3‚THF, the 1,3-diols
were obtained in excellent yield (98%) as a 5-7:1 syn/anti
diastereomeric mixture favoring the desired intermediate 26a.
The relative configuration was determined by acetonide forma-
tion and measurements of the 1H NMR 3J-bond coupling
constants analysis (Scheme 10).
With useful amounts of intermediate 26a obtainable, we
needed a relatively labile protecting group for the primary
hydroxyl that would allow us to obtain the methyl ether of C11.
A trimethylsilyl ether appeared as the group of choice, since it
could be easily removed under mild acidic conditions during
the workup procedure to obtain precursor 29a or be directly
deprotected and oxidized to aldehyde 30 under Swern condi-
tions.23 Treatment of 1,3-diol 26a with TMSCl (1.1 equiv) and
Et3N (2 equiv) in THF at -78 °C for 15 min cleanly afforded
Scheme 11
the primary trimethylsilyl ether 28 in 98% yield. Methylation
of the C11 secondary alcohol was carried out using trimethy-
loxonium tetrafluoroborate (10 equiv) and proton sponge (10
equiv) in CH2Cl2 at room temperature for 2 h. When the
reaction mixture was washed with H2O, 65% of the methylated
product 29a with the TMS group still attached to the primary
position could be isolated. On the other hand, when a 1 N
NaHSO4 solution was used to wash the crude mixture, 86% of
the methylated product 29b with a free primary hydroxyl group
was isolated as the major product. Both intermediates could
be converted, with comparable yields, to the corresponding
aldehyde 5 by means of a Swern oxidation (Scheme 11).
Subsequent treatment of 5 with (carbethoxymethylene)-
triphenylphosphorane24 in refluxing toluene afforded the R,â-
unsaturated ester 30, which was conveniently converted into
R,â-unsaturated aldehyde 4 by sequential DIBAL-H reduction
and Swern oxidation (Scheme 12).
At this stage of the synthesis, an advanced intermediate
bearing five of the seven stereogenic centers and one trisubsti-
tuted double bond had been assembled. The five stereocenters
were introduced through two asymmetric crotylation and one
(23) Maycock, C.; Barros, T.; Afonso, C. J. Chem. Soc., Perkin Trans.
1 1987, 1221-1223.
(24) Kishi, Y.; Johnson, M. R. Tetrahedron Lett. 1979, 20, 4347-4750.

4118 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Panek et al.
Scheme 12
Scheme 13
heteroatom-directed hydroboration or, alternatively, through one
asymmetric crotylation, one heteroatom-directed hydroboration,
and one diastereoselective hydroboration. Thus, we have
established a convergent route to an advanced intermediate that
was elaborated to the seco acid precursor (2) of the macbecin
I macrocycle.
Introduction of the C6/C7 Stereogenic Centers. It was
our intention to introduce the C6/C7 stereocenters with our
crotylation methodology. The successful use of this methodol-
ogy will require the introduction of a oxygen protective group
other than benzyl group. Considering the chemical compatibility
of the various functional groups to strong Lewis acids and
catalytic hydrogenolysis conditions (i.e., competing double-bond
reduction), removal of the C7 benzyl group would be problem-
atic. To circumvent these functional groups compatibility
problems, a protecting group that could be removed under
relatively mild oxidation conditions was investigated. It is well-
precedented that the substituted methoxybenzyl group can be
easily removed by oxidative cleavage [dichlorodicyanobenzo-
quinone (DDQ) or cerium(IV) ammonium nitrate (CAN)];25 the
oxidation potentials of related substituted benzyl alcohols have
been measured by E. A. Mayeda.26 The reactivities of various
substituted benzyl ethers and alcohols toward DDQ and CAN
have also been reported.27
generated oxocarbenium ion addition reaction among intermedi-
ate 4, chiral crotylsilane 9c, and 4-acetoxybenzyl trimethylsilyl
ether in CH2Cl2 at -78 °C for 16-18 h. The adduct 32 was
isolated with a diastereoselection of greater than 20:1 syn/anti
in 92% yield. Subsequent hydrolysis with K2CO3 (2 equiv) in
MeOH, followed by treatment with tBuOK and MeOTf in DMF
at 0 °C to room temperature for 5 h afforded the p-methoxy-
benzyl (PMB)-protected ether in 82% yield over two steps.
Selective cleavage of the trans-disubstituted double bond was
accomplished by OsO4-promoted dihydroxylation reaction with
NMO in tBuOH/THF/H2O (10:3:1) at room temperature for 4-5
h, followed by treatment of the crude diol with K2CO3 (2 equiv)
and Pb(OAc)4 (1.1 equiv) in anhydrous benzene at room
temperature for 5 min, produced the R-methyl aldehyde 3 in
67% yield over two steps (Scheme 13).
Thus far, the C5-C21 macbecin subunit including all seven
stereogenic centers, leaving only the installation of the C1-C4
dienic amide unit has been assembled.
With this information, an investigation of several oxygen
substituted benzyl ethers as possible protecting groups was
undertaken. There were three essential concerns in this study:
(i) an efficient condensation had to be achieved in the three-
component crotylation reaction, (ii) a substituted benzyl func-
tionality with lowest oxidation potential was necessary to
employ the mildest, and most efficient, oxidizing agent, and
(iii) the deprotected allylic alcohol should not be overoxidized
to the ketone.28 Two advantages in using a substituted benzyl
group as a protecting group are (1) protection of the incipient
C7 hydroxy group occurs in the course of crotylation with the
three component system which also installs the C6/C7 stereo-
genic centers and (2) the potential to simultaneously oxidize
the ansamycin aromatic unit to the benzoquinone and remove
the C7-substituted benzyl ether protecting group in a single
operation. Therefore, three candidates were chosen for this
study on the basis of their oxidation potentials. They were
m-methoxybenzyl (1.4 V), 2,3-dimethoxybenzyl (between 1.3
and 1.4 V), and 4-acetoxybenzyl group (∼1.9 V), which can
be easily converted into the 4-methoxybenzyl group (1.3 V).
With the appropriate conditions in hand, the 4-methoxybenzyl
group was chosen for C7 hydroxy protection. The last pair of
stereocenters (C6/C7) was then constructed by an in situ-
Formation of C1-C4 Diene Fragment. Completion of the
Z,E-dienoate system was carried out by a sequential olefination
reaction. A Z-selective Horner-Emmons olefination was
carried out between aldehyde 3 and trifluoroethyl phosphonate
reagent developed by Still and co-workers.29 Treatment of the
phosphonate with KN(TMS)2 and 5 equiv of 18-crown-6 in
anhydrous THF followed by addition of aldehyde 3 in THF
afforded an inseparable mixture of R,â-unsaturated esters 36
(Z/E ) 15:1) in 82% yield. Treatment of the purified esters 36
with DIBAL-H (THF, -78 °C) followed by Swern oxidation
afforded aldehydes 38. The completion of the macbecin
framework was accomplished by treating aldehydes 38 with
(carbethoxymethylene)triphenylphosphorane in refluxing toluene
for 12 h. The E,Z-dienoate 39 was isolated in 97% yield with
an E/Z ratio of 12:1 (Scheme 14).
Nitro Group Reduction. The goal of utilizing the aryl nitro
group, as the masked amine, throughout the entire reaction
sequence was successfully achieved, albeit with some degree
of difficulty. It was now required to reduce this function in
the presence of an R,â,γ,δ-unsaturated ester, a trisubstituted
double bond, a benzylic methyl ether, and a 4-methoxybenzyl
group. In earlier published syntheses of macbecin, the use of
SnCl2,30 aluminum amalgam,31 and palladium on carbon,32
resulted in either low yields or extensive decomposition of the
starting material. The only successful reduction of such aryl
nitro group was accomplished by catalytic hydrogenation with
(25) (a) Yonemitsu, O.; Abe, R.; Nakajima, N. Chem. Pharm. Bull. 1988,
4244-4247. (b) Oikawa, Y.; Tanaka, T.; Horita. K.; Yoshioka, T.;
Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5393-5396. (c) Fukuyama, T.;
Laird, A. A.; Hotchkiss, L. M. Tetrahedron lett. 1985, 26, 6291-6292.
(26) Mayeda, E. A.; Miller, L. L.; Wolf, J. F. J. Am. Chem. Soc. 1972,
6812-6816.
(27) Trahanovsky, W. S.; Young, L. B.; Brown, G. L. J. Org. Chem.
1967, 32, 3865-3868.
(28) Trost, B. M.; Chung, J. Y. L. J. Am. Chem. Soc. 1985, 107, 4586-
4588.
(29) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(30) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-842.
(31) Corey, E. J.; Vlattas, I.; Anderson, N. H.; Harding, K. J. Am. Chem.
Soc. 1968, 90, 3247-3248.
(32) Nakano, M.; Sato, Y. J. Org. Chem. 1987, 52, 1844-1847.

Total Synthesis of (+)-Macbecin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4119
Scheme 14
Scheme 16
Scheme 15
amounts of decarbamoyl macbecin 43. Treatment of this crude
benzoquinone with DDQ (1.5 equiv) in THF/H2O (20:1)
provided decarbamoyl macbecin 43 in 39% yield over two steps.
Finally, acylation of the C7 hydroxyl (NaOCN, TFA) provided
synthetic (+)-macbecin I (1), which agreed in all respects with
the data (1H NMR, 13C NMR, IR, [R]23D, MS, and TLC Rf)
reported in the literature for the natural product [synthetic, [R]23
D
) +341° (c 0.14, CHCl3); natural, Muroi4 [R]D ) +351° (c
0.10, CHCl3)].
Lindlar’s catalyst33 which afforded the anilinic ester in 94%
yield along with 6% of starting material. However, extensive
hydrogenation of the γ,δ-Z double bond was often observed
when the same procedure was applied to ester 39 (Scheme 15).
Conclusions
In the course of this work, the successful total synthesis of
(+)-macbecin I has been achieved in 33 steps with 0.64% overall
yield beginning with crotylsilane 9a and acetal 10. Chiral (E)-
crotylsilane methodology has been pivotal in the control of five
of the seven stereogenic centers within the target (+)-macbecin
I. A diastereoselective hydroboration of the 1,1-disubstituted
terminal allylic alcohol 6b was successfully employed to install
the C10 stereogenic center, and a heteroatom-directed hydrobo-
ration of adduct 8 provided the C12 stereocenter. Therefore,
this report represents the first total synthesis of (+)-macbecin
I without the use of metal enolate-based methodology for the
construction of the stereochemical relationships.
(+)-Macbecin I. The crucial reduction of the aryl nitro group
was finally accomplished by NaBH4 and elemental sulfur
according to the procedures of Lalancette.34 After the mixture
was stirred in refluxing THF for 5 h, the desired anilinic ester
2 was obtained in 99% yield. The steps remaining for the
completion of the synthesis of macbecin are depicted in Scheme
16. The required hydrolysis of the ethyl ester of 2 (LiOH, THF/
MeOH/H2O) provided the amino acid 41 in 92% crude yield.
Macrocyclization according to the conditions of Baker and
Castro using N,N′-bis(2-oxo-3-oxazolidinyl)phosphinic chloride
(BOP-Cl)35 in the presence of diisopropylethylamine (0.001 M
in toluene, 85 °C) provided the fully protected macrocyclic
lactone 42 in 63% yield over two steps. The crucial oxidation
and deprotection step of macrocycle 42 was carried out using
the conditions previously evaluated on the model systems.
Oxidation of macrocycle 42 by CAN (7.5 equiv) in MeCN/
H2O (10:1) at -10 °C for 30 min led to extensive decomposition
of the starting material, and only a trace amount of decarbamoyl
(+)-macbecin 43 could be observed. Oxidation of the macro-
cycle by CAN (5 equiv) in THF/H2O (10:1) at -10 °C provided
a reasonably clean benzoquinone product with only trace
Experimental Section
Methyl (2S,3E,5S,6R)-2-(Benzyloxy)-6-(2,5-dimethoxy-3-nitro-
phenyl)-6-methoxy-5-methyl-3-hexenoate (8). A cooled (-78 °C)
solution of 7.20 g (27.7 mmol) of the 2,5-dimethoxy-3-nitrobenzyl
dimethyl acetal 10 and 10.18 g (27.6 mmol) of (2R,3R,4E)-2-
(benzyloxy)-3-(dimethylphenylsilyl)hexenoate 9a in 60 mL of anhy-
drous CH2Cl2 was treated with 2.5 mL (13.5 mmol) of (trimethylsilyl)-
trifluoromethanesulfonate (TMSOTf) dropwise. The resulting deep red
solution was stirred at -78 °C for 16 h, before it was diluted with 60
mL of saturated NaHCO3 solution and stirred for 15 min at rt. The
layers were separated, and the aqueous layer was extracted with two
portions of 30 mL of CH2Cl2. The combined yellow organic phases
were washed with 50 mL of brine, dried over MgSO4, filtered, and
concentrated. Purification of the residue by chromatography (solvent
gradient: 10% EtOAc/PE to 40% EtOAc/PE) afforded 11.0 g (89%)
of pure desired adduct 8 (de > 96%) as a yellow solid: [R]23D ) +77.6°
(33) Corey, E. J.; Nicolaou, K. C.; Balanson, R. D.; Machida, Y. Synthesis
1975, 590-591.
(34) (a) Lalancette, J. M.; Freche, A.; Brindle, J. R.; Laliberte, M.
Synthesis, 1972, 527-532. (b) Lalancettte, J. M.; Freche, A.; Monteux, R.
Can. J. Chem. 1968, 46, 2754-2757.
(35) (a) Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J.
R. Synthesis 1980, 547-551. (b) Van Der Auwera, C.; Anteunis, M. J. O.
Int. J. Peptide Protein Res. 1987, 29, 574-588.
1
(c 1.91, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.34-7.27 (m, 6H),
7.14 (d, 1H, J ) 3.6 Hz), 5.79-5.74 (dd, 1H, J ) 8.0, 15.6 Hz), 5.43-

4120 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Panek et al.
5.37 (dd, 1H, J ) 6.8, 15.6 Hz), 4.51 (d, 2H, J ) 3.2 Hz), 4.40 (d, 1H,
J ) 6.8 Hz), 4.30 (d, 1H, J ) 6.8 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 3.68
(s, 3H), 3.24 (s, 3H), 2.55-2.53 (m, 1H), 1.10 (d, 3H, J ) 6.8 Hz);
13C NMR (67.5 MHz, CDCl3) δ 171.1, 155.2, 145.5, 143.5, 138.2,
137.2, 137.1, 128.3,127.9, 127.8, 125.4, 118.6, 109.0, 80.5, 78.2, 70.9,
62.7, 57.3, 55.9, 52.0, 43.0, 15.5; IR (neat) νmax 3100, 2995, 1750,
Hz), 0.76 (d, 3H, J ) 7.2 Hz); 13C NMR (67.5 MHz, CDCl3) δ 171.9,
154.9, 145.4, 143.5, 138.8, 136.8, 121.8, 118.7, 108.4, 84.1, 81.6, 80.6,
62.6, 60.5, 57.4, 56.9, 55.8, 51.6, 39.3, 37.7, 35.1, 33.2, 16.9, 13.1; IR
(neat) νmax 2990, 2860, 1750, 1650, 1550, 1500, 1450; CIHRMS M +
+
NH4 501.2833 (C24HN2O7 requires 501.2812).
(2R,3R,4S,6S,7R)-7-(2,5-Dimethoxy-3-nitrophenyl)-3,4,7-trimethoxy-
2,6-dimethylheptanal (5). Into a cooled (-78 °C) solution of 1.37 g
(2.75 mmol) of olefin 15 and 0.2 mL (2.5 mmol) of pyridine in methanol
was bubbled ozone gas until the solution turned blue in color (ca. 15
min). The reaction mixture was then quenched with 1.6 mL (21.8
mmol) of Me2S and allowed to warm to rt. After being stirred at
ambient temperature for 14 h, the reaction mixture was concentrated.
Purification of the remaining residue (solvent gradient: 10% EtOAc/
+
1620, 1580, 1530, 1490, 1430; CIHRMS M + NH4 477.2267
(C24H33N2O8 requires 477.2237).
(2R,3S,5S,6R)-2-(Benzyloxy)-6-(2,5-dimethoxy-3-nitrophenyl)-6-
methoxy-5-methylhexa-1,3-diol (11). A cooled (0 °C) solution of 11.0
g (24.7 mmol) of 8 in 300 mL of anhydrous THF was treated with 2.6
mL of BH3‚SMe2 (10 M, 26.0 mmol) dropwise over 10 min. The
resulting reaction mixture was allowed to warm to rt over 2 h and stirred
for 16 h at rt, before it was cooled to 0 °C. The solution was then
diluted with 10 mL of MeOH followed by NaOOH (4 equiv, 20 mL,
5 M NaOH aqueous solution; 11.3 mL, 30% H2O2) oxidation. The
reaction mixture was stirred at 0 °C for 30 min and 90 min at rt, before
it was diluted with 30 mL of 5% aqueous HCl solution. The layers
were separated, and the aqueous layer was extracted with four portions
of 50 mL of EtOAc. The combined organic phases were washed with
100 mL of brine, dried over MgSO4, filtered, and concentrated.
Purification of the residue by chromatography (solvent gradient: 30%
EtOAc/PE to 100% EtOAc) afforded 8.1 g of pure anti-1,3-diol 11
PE to 30% EtOAc/PE) afforded 0.73 g (65%) of desired aldehyde 5 as
1
a yellow oil: [R]23 ) +47.7° (c 1.1, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 9.71 (d, 1H, J ) 1.2 Hz), 7.30 (d, 1H, J ) 3.2 Hz), 7.18 (d,
1H, J ) 3.2 Hz), 4.46 (d, 1H, J ) 4.8 Hz), 3.87 (s, 3H), 3.86 (s, 3H),
3.61-3.58 (dd, 1H, J ) 4.8, 6.0 Hz), 3.35 (s, 6H), 3.33-3.29 (obscured
m, 1H), 3.28 (s, 3H), 2.66-2.64 (m, 1H), 2.03-2.00 (m, 1H), 1.63-
1.55 (m, 2H), 1.19 (d, 3H, J ) 7.2 Hz), 0.91 (d, 3H, J ) 6.8 Hz); 13
C
NMR (67.5 MHz, CDCl3) δ 203.4, 155.0, 145.4, 143.5, 138.6, 118.7,
108.6, 81.7, 81.3, 79.5, 62.6, 59.2, 57.7, 57.5, 55.9, 48.3, 35.5, 35.1,
13.9, 8.7; IR (neat) νmax 2910, 2800, 1710, 1620, 1570, 1510, 1470,
1420; CIHRMS M + NH4+ 431.2401 (C20H35N2O8 requires 431.2393).
(2S,3E,5S,6R)-7-(2,5-Dimethoxy-3-nitrophenyl)-4,7-dimethoxy-
2,6-dimethyl-1-ene-3-heptanol (6b). To a solution of 25 (2.50 g, 5.0
mmol, 1.0 equiv) in 25.1 mL of CH3CN was added 5.1 mL of 48%
aqueous HF. The reaction was stirred at room temperature for 1 h
before it was diluted with 50 mL of saturated NaHCO3, extracted with
CH2Cl2 (3 × 20 mL), washed with BRINE (100 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the residue
by column chromatography (30% EtOAc/PE) afforded 1.92 g (100%)
along with 1.01 g of syn-1,3-diol in 85% as a viscous yellow oil: [R]23
D
1
) +27.0° (c 0.2, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.36-7.28
(m, 5H), 7.27 (d, 1H, J ) 2.8 Hz), 7.14 (d, 1H, J ) 2.8 Hz), 4.62
(ABq, 2H, J ) 11.6 Hz), 4.52 (d, 1H, J ) 4.8 Hz), 3.84-3.82 (m,
1H), 3.81 (s, 6H), 3.81-3.77 (m, 2H), 3.33-3.25 (m, 1H), 3.25 (s,
3H), 2.46 (d, 1H, J ) 4.0 Hz), 2.21-2.18 (t, 1H, J ) 5.6 Hz), 2.05-
2.02 (m, 1H), 1.55-1.46 (m, 2H), 0.84 (d, 3H, J ) 6.8 Hz); 13C NMR
(67.5 MHz, CDCl3) δ 154.8, 145.1, 143.3, 138.2, 137.8, 128.1,127.5,
127.4, 118.5, 108.4, 81.8, 81.1, 71.6, 69.2, 62.4, 60.7, 57.08, 55.5, 36.5,
35.4, 13.5; IR (neat) νmax 3450, 2970, 1540, 1480, 1430; CIHRMS M
of allylic alcohol 6b as a bright yellow oil: [R]23 ) +72.4° (c 1.18,
D
+
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 1H, J ) 3.2 Hz), 7.13
(d, 1H, J ) 3.2 Hz), 5.07 (bs, 1H), 4.90 (bs, 1H), 4.42 (d, 1H, J )
4.8), 4.33 (bs, 1H), 3.81 (s, 6H), 3.37 (s, 3H), 3.33-3.29 (m, 1H),
3.21 (s, 3H), 2.21 (d, 1H, J ) 2.3 Hz), 2.0-1.92 (m, 1H), 1.68 (s,
3H), 1.61-1.54 (m, 1H), 1.31-1.23 (m, 1H), 0.80 (d, 3H, J ) 7.2
Hz); 13C NMR (67.5 MHz, CDCl3) δ 155.0, 145.5, 143.6, 143.0, 138.8,
118.8, 111.6, 108.7, 81.4, 80.3, 73.1, 62.7, 57.5, 57.3, 55.9, 35.1, 31.8,
19.5, 13.6; IR (neat) νmax 3854, 3744, 3019, 1734, 1700, 1685, 1653,
1617, 1576, 1480, 1457; CIHRMS M + NH4+ (calcd for C19H33N2O7)
401.2289, found 401.2298.
+ NH4 467.2400 (C23H35N2O8 requires 467.2393).
(2S,4S,5R)-5-(2,5-Dimethoxy-3-nitrophenyl)-2,5-dimethoxy-4-me-
thylpentanal (6a). A solution of 2.20 g (6.13 mmol) of 1,2-diol 7 in
60 mL of acetone/H2O (1:1) was treated with 1.54 g of NaHCO3 (18.33
mmol) and 2.0 g of NaIO4 (9.35 mmol). The resulting solution was
stirred at ambient temperature for 100 min before it was diluted with
50 mL of H2O. The aqueous layer was extracted three times with 50
mL of Et2O. The combined organic phases were dried over MgSO4,
filtered, and concentrated. Purification of the residue (5% EtOAc/PE
to 20% EtOAc/PE) afforded 1.69 g (84%) of desired aldehyde 6a as a
1
yellow oil: [R]23 ) +7.3° (c 0.85, CH2Cl2); H NMR (400 MHz,
(2R,3R,4S,6S,7R)-7-(2,5-Dimethoxy-3-nitrophenyl)-4,7-dimethoxy-
2,6-dimethylhepta-1,3-diol (26a). A cooled (-5 °C) solution of 1.92
g (5.0 mmol) of 8g in 50.1 mL of anhydrous THF was treated with 20
mL of BH3‚THF (1.0 M, 20.0 mmol, 4.0 equiv) dropwise over 10 min.
The resulting reaction mixture was kept at -5 °C for 45 min. The
solution was then diluted with 5 mL of MeOH followed by NaOOH
(1.5 equiv, 2.50 mL, 3 M NaOH aqueous solution; 0.83 mL of 30%
H2O2) oxidation. The reaction mixture was stirred at 0 °C for 30 min
and 90 min at rt, before it was diluted with 20 mL of H2O. The layers
were separated, the aqueous layer was extracted with four portions of
50 mL of EtOAc. The combined organic phases were washed with
100 mL of brine, dried over MgSO4, filtered, and concentrated.
Purification of the residue by chromatography (solvent gradient: 30%
EtOAc/PE to 100% EtOAc) afforded 1.76 g of pure 1,3-diol 26a along
with 0.25 g of the diastereomer 1,3-diol 26b as a viscous yellow oil:
[R]23D ) +71.9° (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27
(d, 1H, J ) 3.6 Hz), 7.15 (d, 1H, J ) 3.6 Hz), 4.46 (d, 1H, J ) 4.6
Hz), 3.83 (s, 3H), 3.82 (s, 3H), 3.78-3.73 (m, 1H), 3.67-3.62 (m,
2H), 3.33 (s, 3H), 3.32-3.29 (obscured m, 1H), 3.24 (s, 3H), 2.46 (d,
1H, J ) 3.2 Hz), 2.04-2.01 (m, 1H), 1.87-1.84 (m, 1H), 1.73-1.63
(m, 2H), 1.52-1.48 (m, 1H), 1.02 (d, 3H, J ) 6.9 Hz), 0.85 (d, 3H, J
) 6.6 Hz); 13C NMR (67.5 MHz, CDCl3) δ 155.1, 145.5, 143.6, 138.5,
118.9, 108.6, 81.5, 79.9, 73.7, 66.8, 62.7, 57.5, 57.4, 55.9, 36.1, 34.9,
33.2, 14.2, 11.5; IR (neat) νmax 3425, 2937, 2829, 1653, 1576, 1533,
1481; CIHRMS M + H+ (calcd for C19H32NO8) 402.2128, found
402.2126.
D
CDCl3) δ 9.62 (d, 1H, J ) 2.0 Hz), 7.26 (d, 1H, J ) 3.2 Hz), 7.12 (d,
1H, J ) 3.2 Hz), 4.43 (d, 1H, J ) 4.8 Hz), 3.82 (s, 3H), 3.81 (s, 3H),
3.64-3.59 (m, 1H), 3.41 (s, 3H), 3.22 (s, 3H), 2.06-2.02 (m, 1H),
1.71-1.64 (m, 1H), 1.59-1.54 (m, 1H), 0.86 (d, 3H, J ) 6.8 Hz); 13
C
NMR (67.5 MHz, CDCl3) δ 203.5, 155.0, 145.2, 143.5, 138.2, 118.7,
108.6, 84.0, 80.7, 62.6, 58.2, 57.4, 55.9, 34.9, 33.2, 13.3; IR (neat)
+
ν
max 3000, 2860, 1750, 1650, 1550, 1500, 1450; CIHRMS M + NH4
359.1829 (C16H27N2O7 requires 359.1818).
Methyl (3E,5S,6R,7S,9S,10R)-10-(2,5-Dimethoxy-3-nitrophenyl)-
6,7,10-trimethoxy-5,9-dimethyl-3-decenoate (15). To a cooled (-78
°C) solution of 1.69 g (5.15 mmol) aldehyde 6a, 1.07 g (10.27 mmol)
of TMSOMe, and (4E,3S)-3-(dimethylphenylsilyl)hexenoate 9b in 10
mL of anhydrous CH2Cl2 was added 1.9 mL (10.3 mmol) of TMSOTf.
The resulting solution was stirred at -78 °C for 18 h and then allowed
to warm to -50 °C. After being stirred for 24 h at -50 °C, the reaction
solution was diluted with 20 mL of saturated NaHCO3 aqueous solution.
The aqueous phase was extracted three times with 30 mL of CH2Cl2.
The combined organic phases were dried over MgSO4, filtered, and
concentrated. Purification of the residue (solvent gradient: 10% EtOAc/
PE to 30% EtOAc/PE) afforded 2.05 g (80%) of adducts 15 (∼15:1
syn/anti at C10/C11) as a yellow oil: [R]23D ) +38.5° (c 1.07, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.26 (d, 1H, J ) 3.2 Hz), 7.15 (d, 1H,
J ) 3.2 Hz), 5.54-5.49 (m, 1H), 5.44-5.38 (m, 1H), 4.43 (d, 1H, J )
4.4 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 3.64 (s, 3H), 3.44 (s, 3H), 3.29 (s,
3H), 3.25-3.21 (m, 1H), 3.21 (s, 3H), 3.12-3.07 (dd, 1H, J ) 7.6,
14.4 Hz), 3.00 (d, 2H, J ) 7.2 Hz) 2.30-2.25 (m, 1H), 2.01-1.94 (m,
1H), 1.66-1.63 (m, 1H), 1.45-1.39 (m, 1H), 1.06 (d, 3H, J ) 6.4
(2R,3R,4S,6S,7R)-7-(2,5-Dimethoxy-3-nitrophenyl)-4,7-dimethoxy-
2,6-dimethyl-1-((trimethylsilyl)oxy)-3-heptanol (28). To a stirred

Total Synthesis of (+)-Macbecin I
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4121
solution of diol 26a (1.76 g, 4.4 mmol) in 21.9 mL of anhydrous THF
(0.2 M) at -78 °C was added Et3N (1.22 mL, 8.8 mmol, 2.0 equiv)
followed by addition of TMSCl (0.91 mL, 4.8 mmol, 1.1 equiv). The
reaction was kept at -78 °C for 15 min before it was diluted with 20
mL of H2O. The reaction mixture was extracted with Et2O (3 × 15
mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification
166.3, 158.9, 154.9, 152.3, 145.4, 143.6, 138.9, 133.1, 131.9, 130.5,
129.0, 128.5, 118.8, 113.6, 108.5, 87.1, 84.3, 81.7, 81.3, 69.4, 62.6,
60.7, 57.5, 56.8, 55.9, 55.2, 50.9, 35.5, 35.2, 34.8, 33.1, 17.7, 15.9,
13.2, 12.2; IR (neat) νmax 2970, 1720, 1650, 1620, 1580, 1530, 1450;
+
CIHRMS M + NH4 705.3991 (C37H57N2O11 requires 705.3962).
Ethyl (2E,4Z,6S,7R,8E,10S,11R,12S,14S,15R)-7-(4′-Methoxyben-
zyl)-15-(3-amino-2,5-dimethoxyphenyl)-11,12,15-trimethoxy-2,6,8,-
10,14-pentamethyl-2,4,8-pentadecatrinoate (2). To a mixture of 15
mg (0.4 mmol) of solid NaBH4 and 45 mg (1.4 mmol) of sulfur was
added 3 mL of anhydrous THF dropwise. After the mixture was stirred
for 5 min (most of the solid has dissolved), 48 mg (0.065 mmol) of
starting nitro compound 39 was added in 1 mL of THF (followed by
0.5-mL rinse twice). After refluing for 5 h, the reaction mixture was
cooled to rt and diluted with 2 mL of NaOH (2 M) aqueous solution
and 5 mL of H2O. The aqueous layer was extracted three times with
10 mL of Et2O and two times with 10 mL of EtOAc, dried over MgSO4,
filtered, and concentrated. Purification of the residue (solvent gradi-
on SiO2 (20% EtOAc/PE) afforded 2.03 g (98%) of the pure silyl ether
1
28 as a yellow oil: [R]23 ) +55.9° (c 0.71, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.26 (d, 1H, J ) 3.3 Hz), 7.16 (d, 1H, J ) 3.3 Hz),
4.44 (d, 1H, J ) 4.6 Hz), 3.83 (s, 3H), 3.81 (s, 3H), 3.73-3.70 (m,
1H), 3.61 (ABq, 2H, JAB)4.0 Hz), 3.32 (s, 3H), 3.29-3.25 (obscured
m, 1H), 3.23 (s, 3H), 2.84 (bs, 1H), 2.06-2.01 (m, 1H), 1.86-1.83
(m, 1H), 1.61-1.52 (m, 2H), 0.99 (d, 3H, J ) 6.9 Hz), 0.88 (d, 3H, J
) 6.6 Hz), 0.09 (s, 9H); 13C NMR (67.5 MHz, CDCl3) δ 155.1, 145.6,
143.6, 138.9, 118.9, 108.6, 81.6, 79.7, 77.4, 76.6, 74.6, 67.4, 62.7, 57.5,
57.4, 55.9, 35.4, 35.1, 34.1, 33.8, 22.3, 14.1, 14.0, 11.5, -0.7; IR (neat)
ν
max 3688, 3468, 3020, 2400, 1710, 1533, 1479, 1427; CIHRMS M +
H+ (calcd for C22H40NSiO8) 474.2523, found 401.2518.
ent: 20% to 50% EtOAc/PE) afforded 46 mg (99%) of desired anilinic
1
ester 2 as a light yellow oil: [R]23 ) +73.7° (c 0.27, CH2Cl2); H
(3E,5S,6R,7E,9S,10R,11S,13S,14R)-6-(4′-Acetoxybenzyl)-14-(2,5-
dimethoxy-3-nitrophenyl)-1,10,11,14-tetramethoxy-5,7,9,13-tetra-
methyl-3,7-tetradecadiene (32). A cooled (-78 °C) solution of 0.27
g (0.904 mmol) of 4-acetoxybenzyl trimethylsilyl ether, 0.212 g (0.906
mmol) of (2E,4S)-4-(dimethylphenylsilyl)-6-methoxyhexene 9c, and
0.342 g (0.755 mmol) of aldehyde 4 in 2 mL of anhydrous CH2Cl2
was treated with 0.07 mL (0.38 mmol) of TMSOTf dropwise. The
resulting solution was stirred for 18 h before it was quenched by 5 mL
of saturated NaHCO3 aqueous solution. The aqueous layer was
extracted three times with 10 mL of CH2Cl2, and the combined organic
phases were dried over MgSO4, filtered, and concentrated. Purification
of the residue (solvent gradient: 10% EtOAc/PE to 30% EtOAc/PE)
D
NMR (400 MHz, CDCl3) δ 7.40 (d, 1H, J ) 11.6 Hz), 7.21 (d, 2H, J
) 8.8 Hz), 6.85 (d, 2H, J ) 8.8 Hz), 6.38 (br s, 2H), 6.11 (t, 1H, J )
11.6 Hz), 5.48 (t, 1H, J ) 10.4 Hz), 5.21 (d, 1H, J ) 9.6 Hz), 4.31
(ABq, 2H, J ) 11.2 Hz), 4.32 (d, 1H, J ) 4.8 Hz), 4.19-4.11 (m,
3H), 3.80 (obscured m, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H),
3.43 (s, 3H), 3.37 (d, 1H, J ) 8.8 Hz), 3.26 (s, 3H), 3.21 (s, 3He),
3.19-3.17 (m, 1H), 3.15-3.08 (dd, 1H, J ) 2.4, 8.0 Hz), 3.06-2.97
(m, 1H), 2.53-2.49 (m, 1H), 2.02-1.91 (m, 1H), 1.81 (d, 3H, J ) 1.6
Hz), 1.76-1.64 (m, 1H), 1.50 (s, 3H), 1.36-1.29 (m, 1H), 1.27 (t,
3H, J ) 6.8 Hz), 1.06 (d, 3H, J ) 6.8 Hz), 1.05 (d, 3H, J ) 6.8 Hz),
0.75 (d, 3H, J ) 6.8 Hz); 13C NMR (67.5 MHz, CDCl3) δ 168.4, 159.0,
156.2, 140.9, 140.0, 139.9, 134.9, 133.6, 132.9, 132.2, 130.5, 129.3,
127.9, 123.2, 113.7, 101.6, 101.1, 88.2, 84.8, 82.2, 81.1, 69.3, 60.6,
60.5, 59.8, 57.2, 56.8, 55.3, 55.2, 35.8, 35.5, 34.6, 33.3, 18.0, 17.5,
14.3, 14.0, 12.3, 11.8; CIHRMS M+ 711.4313 (C41H61NO9 requires
711.4346).
(2E,4Z,6S,7R,8E,10S,11R,12S,14S,15R)-7-(4′-Methoxybenzyl)-15-
(2,5-dimethoxy-3-nitrophenyl)-11,12,15-trimethoxy-2,6,8,10,14-pen-
tamethyl-2,4,8-pentadecatrienoic Acid (41). To a solution of 35 mg
(0.049 mmol) of anilinic ester 2 in 10 mL of 2:2:1 MeOH/THF/H2O
was added 41 mg (0.98 mmol) of solid LiOH‚H2O. The reaction
mixture was stirred at ambient temperature for 48 h. The mixture was
concentrated to remove the MeOH and THF and then dissolved in 30
mL of pH 4.5 NaH2PO4 solution. The mixture was extracted with five
30-mL portions of CH2Cl2, with the aqueous layer being saturated with
solid NaCl between each extraction. The combined organic layers were
dried over MgSO4, filtered, and concentrated to afford 31 mg (92%)
of crude desired aniline acid 41 as a pale yellow glass. This material
was used in the next step without further purification.
(4E,6Z,8S,9R,10E,12S,13R,14S,16S,17R)-9-(4′-Methoxybenzyl)-
13,14,17,20,22-pentamethoxy-4,8,10,12,16-pentamethyl-2-azabicyclo-
[16.3.1]docosa-1(22),4,6,10,18,20-hexaen-3-one (42). To a heated
solution (85 °C) of 31 mg (0.045 mmol) of crude amino acid 41 and
160 µL (0.92 mmol) of Hu¨nig’s base in 55 mL of anhydrous PhCH3
was added 92 mg (0.36 mmol) of BOP-Cl. The solution was stirred at
this temperature for 12 h before it was cooled to rt and poured into 50
mL of pH 4.5 NaH2PO4 solution. The layers were separated, and the
aqueous layer was extracted with three 30-mL portions of Et2O. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. Purification of the residue by chromatography (solvent
gradient: 20% to 40% EtOAc/PE) afforded 20 mg (63%) of desired
macrocycle 42 as a clear glass: 1H NMR (400 MHz, DMSO) δ 9.30
(s, 1H), 7.15 (d, 2H, J ) 8.0 Hz), 6.88 (d, 2H, J ) 8.0 Hz), 6.61 (d,
1H, J ) 3.2 Hz,H), 6.44 (d, 1H, J ) 3.2 Hz), 5.93 (d, 1H, J ) 12.0
Hz), 5.78 (t, 1H, J ) 11.2 Hz), 5.03 (t, 1H, J ) 10.4 Hz), 4.92 (d, 1H,
J ) 10.0 Hz), 4.35 (d, 1H, J ) 5.2 Hz), 4.10 (ABq, 2H, J ) 11.6 Hz),
3.73 (s, 3H), 3.68 (s, 3H), 3.42 (s, 3H), 3.40 (s, 3H), 3.21 (s, 3H), 3.17
(obscured d, 1H, J ) 9.6 Hz), 3.16 (s, 3H), 3.15-3.08 (m, 1H), 2.85
(m, 1H), 2.52-2.49 (m, 1H), 2.15-2.12 (m, 2H), 1.79 (s, 3H), 1.51-
1.48 (m, 1H), 1.00 (d, 3H, J ) 6.8 Hz), 0.94 (s, 3H), 0.85 (d, 3H, J )
6.8 Hz), 0.58 (d, 3H, J ) 6.8 Hz); CIHRMS M + H+ 666.4002 (C39H56-
NO8 requires 666.4006).
afforded 0.5 g (92%) of desired addition product 32 (de > 20:1) as a
1
yellow oil: [R]23 ) +42.5° (c 0.40, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 7.28 (d, 1H, J ) 8.4 Hz, 2H), 7.25 (d, 1H, J ) 3.2 Hz), 7.16
(d, 1H, J ) 3.2 Hz), 7.01 (d, 2H, J ) 8.4 Hz,), 5.37-5.33 (m, 2H),
5.20 (d, 1H, J ) 9.6), 4.45 (d, 1H, J ) 4.4 Hz), 4.31 (ABq, 2H, J )
12.4 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 3.43 (s, 3H), 3.32-3.27 (m, 3H),
3.26 (s, 3H), 3.25 (s, 3H), 3.22 (s, 3H), 3.19-3.16 (m, 1H), 3.10-
3.08 (dd, 1H, J ) 2.1, 8.0 Hz), 2.57-2.51 (m, 1H), 2.38-2.28 (m,
1H), 2.27 (s, 3H), 2.18-2.11 (m, 2H), 2.05-1.96 (m, 1H), 1.74-1.65
(m, 1H), 1.55 (d, 3H, J ) 1.2 Hz), 1.44-1.38 (m, 1H), 1.05 (d, 3H, J
) 6.8 Hz), 1.01 (d, 3H, J ) 6.8 Hz), 0.77 (d, 3H, J ) 6.8 Hz); 13C
NMR (67.5 MHz, CDCl3) δ 169.5, 154.9, 149.8, 145.5, 143.6, 138.9,
136.4, 134.5, 132.8, 132.6, 128.5, 125.7, 121.3, 118.8, 108.5, 88.4,
84.6, 81.8, 80.9, 72.5, 69.0, 62.7, 60.7, 58.4, 57.5, 56.9, 55.9, 39.7,
35.1, 34.7, 33.6, 33.1, 21.1, 17.4, 16.6, 13.4, 12.5; IR (neat) νmax 2970,
+
1760, 1530, 1480, 1460, 1430; CIHRMS M + NH4 734.4301
(C39H62N2O11 requires 734.4353).
Methyl (2Z,4S,5R,6E,8S,9R,10S,12S,13R)-5-(4′-Methoxybenzyl)-
13-(2,5-dimethoxy-3-nitrophenyl)-9,10,13-trimethoxy-4,6,8,12-tet-
ramethyl-2,6-tridecadienoate (36). To a cooled (-78 °C) solution
of 450 mg (1.7 mmol) of 18-crown-6 ether and 160 mg (0.5 mmol) of
bis(2,2,2-trifluoroethyl)phosphonoacetate in 5 mL of anhydrous THF
was added 1.1 mL (0.55 mmol) of KN(TMS)2 (0.5 M in toluene). The
resulting solution was stirred for 5 min, before 211.4 mg (0.343 mmol)
of starting aldehyde 3 in 1.5 mL of anhydrous THF (0.5 mL rinse)
was added. The reaction mixture was stirred for 3 h at -78 °C, before
it was quenched with saturated NH4Cl aqueous solution. The aqueous
layer was extracted three times with 10 mL of Et2O, dried over MgSO4,
filtered, and concentrated to provide a mixture of 15:1 Z/E olefin
products. Purification of the residue (solvent gradient: 15%-30%
EtOAc/PE) afforded 192.5 mg (82%) of desired Z olefin 36 as a yellow
1
oil: [R]23 ) +75.0° (c 1.8, CH2Cl2); H NMR (400 MHz, CDCl3) δ
D
7.24 (d, 1H, J ) 3.6 Hz), 7.19 (d, 2H, J ) 8.8 Hz), 7.15 (d, 1H, J )
3.6 Hz), 6.83 (d, 2H, J ) 8.8 Hz), 5.97-5.92 (dd, 1H, J ) 10.4, 11.6
Hz), 5.60 (d, 1H, J ) 11.6 Hz), 5.19 (d, 1H, J ) 10.4 Hz), 4.44 (d,
1H, J ) 4.0 Hz), 4.40 (ABq, 2H, J ) 11.2 Hz), 3.80 (s, 3H), 3.79 (s,
3H), 3.77 (s, 3H), 3.59 (s, 3H), 3.43 (s, 3H), 3.41-4.39 (obscured m,
1H), 3.23 (s, 3H), 3.20 (s, 3H), 3.19-3.09 (m, 2H), 2.53-2.45 (m,
2H), 2.02-1.95 (m, 1H), 1.73-1.65 (m, 1H), 1.53 (d, 3H, J ) 0.8
Hz), 1.40-1.32 (m, 1H), 1.05 (d, 3H, J ) 6.8 Hz), 1.01 (d, 3H, J )
6.8 Hz), 0.69 (d, 3H, J ) 7.2 Hz); 13C NMR (67.5 MHz, CDCl3) δ

4122 J. Am. Chem. Soc., Vol. 120, No. 17, 1998
Panek et al.
Decarbamoyl Macbecin (43). To a cooled (-10 °C) solution of
22 mg (0.033 mmol) starting macrocycle 42 in 10 mL of 10:1 THF/
H2O was added 170 µL of 1 N ceric ammonium nitrate (CAN) aqueous
solution. The resulting solution was stirred at -10 °C for 30 min,
before it was poured onto 50 mL of H2O. The aqueous layer was
extracted two times with 15 mL of Et2O and three times with 15 mL
of CH2Cl2, and the combined organic layers were dried over MgSO4,
filtered, and concentrated. The crude residue was dissolved in 10 mL
of 20:1 THF/H2O at 0 °C and treated with 11 mg (0.048 mmol) of
DDQ. The resulting solution was stirred at 0 °C for 40 min, before it
was diluted with 10 mL of H2O. The aqueous layer was extracted two
times with 15 mL of Et2O and three times with 15 mL of CH2Cl2,
dried over MgSO4, filtered, and concentrated. Purification of the residue
organic phases were dried over MgSO4 and filtered. Purification by
preparative TLC (Et2O) affored 2.8 mg (51%) of synthetic (+)-macbecin
I: [R]23D ) +341° (c 0.14, CHCl3); lit.4 [R]D ) +351° (c 0.10, CHCl3);
lit.7 [R]D ) +377° (c 0.10, CHCl3); lit.8a [R]D ) +348° (c 0.11, CHCl3);
1H NMR (400 MHz, CDCl3) δ 8.88 (br s, 1H), 7.33 (d, 1H, J ) 2.5
Hz), 7.12 (d, 1H, J ) 11.7 Hz), 6.60 (dd, 1H, J ) 1.5, 2.5 Hz), 6.33
(dd, 1H, J ) 1.8, 12.1 Hz), 5.80 (br s, 1H), 5.66 (dd, 1H, J ) 6.8, 10.7
Hz), 5.25 (br s, 1H), 4.69 (br s, 2H), 4.57 (s, 1H), 3.54 (br s, 1H), 3.52
(s, 3H), 3.32 (s, 3H), 3.29 (s, 3H), 3.25 (m, 1H), 3.08 (m, 1H), 2.48
(m, 1H), 1.98 (s, 3H), 1.68 (m, 2H), 1.49 (m, 1H), 1.48 (s, 3H), 1.08
(d, 3H, J ) 6.5 Hz), 1.02 (d, 3H, J ) 7.0 Hz), 0.79 (d, 3H, J ) 7.0
Hz); 13C NMR (125 MHz, CDCl3) δ 187.8, 184.0, 169.1, 155.7, 144.8,
141.1, 138.2, 133.2, 132.2, 131.6, 128.9, 124.1, 112.8, 83.6, 79.2, 77.1
(obscured), 60.1, 58.2, 55.6, 34.7 (br), 33.9, 33.5 (br), 17.3 (br), 14.9,
13.3, 13.1, 12.3; IR (CHCl3) 3690, 3540, 3420, 3360, 2990, 2930, 1740,
1690, 1665, 1650, 1610, 1585, 1505, 1460, 1375, 1325, 1240, 1210,
1175, 1155, 1095, 1070, 1030; CIHRMS M+ 576.3265 (C30H46N3O8
requires 576.3285).
by preparative TLC (Et2O) afford 4.9 mg (39%) of desired decarbamoyl
1
macbecin 43 as a yellow glass: [R]23 ) +198° (c 0.12 CH2Cl2); H
D
NMR (400 MHz, CDCl3) δ 8.63 (br s, 1H,), 7.32 (d, 1H, J ) 2.4 Hz),
7.13 (d, 1H, J ) 11.6 Hz), 6.63 (t, 1H, J ) 1.7 Hz), 6.38 (t, 1H, J )
11.9 Hz), 5.86 (t, 1H, J ) 7.2 Hz), 5.51(d, 1H, J ) 9.3 Hz), 4.61 (br
s, 1H), 4.55 (s, 1H), 3.53(s, 3H), 3.52 (obscured s, 1H), 3.35 (s, 3H),
3.31 (s, 3H), 3.26 (d, 1H, J ) 9.4 Hz), 3.03 (m, 1H), 2.48 (m, 1H),
2.00 (s, 3H), 1.68 (m, 3H), 1.47 (s, 3H), 1.09 (d, 3H, J ) 6.4 Hz),
0.97 (d, 3H, J ) 7.0 Hz), 0.78 (d, 3H, J ) 7.0 Hz); 13C NMR (67.5
MHz, CDCl3) δ 187.6, 184.3, 168.7, 144.9, 143.7, 138.1, 134.9, 133.1,
132.4, 129.3, 127.9, 123.5, 112.9, 83.7, 83.3, 78.0, 76.8, 60.6, 58.4,
55.5, 38.1, 35.0, 34.0, 29.7, 17.8, 15.1, 13.1, 12.3, 11.9; CIHRMS M+
516.2977 (C29H42NO7 requires 516.2961).
Acknowledgment. Financial support was obtained from
NIH/NCI (RO1 CA56304). We are grateful to Prof. Scott Miller
and Prof. David Evans for their insightful discussions and Prof.
Amir Hoveyda for his helpful discussions on the Rh(I)-catalyzed
hydroboration.
Supporting Information Available: 1H and 13C spectral
data for all intermediates as well as full spectral data for all
compounds not listed in the Experimental Section (95 pages,
print/PDF). See any current masthead page for ordering
information and Web access instructions.
(+)-Macbecin I (1). To a cooled (0 °C) solution of 4.9 mg (9.5
µmol) of quinone 43 in anhydrous CH2Cl2 were added 15.4 mg (237
µmol) of sodium cyanate and 18 µL (234 µmol) of trifluoroacetic acid.
The mixture was stirred at 0 °C for 15 min and at ambident temperature
for 4.5 h before the solution was diluted with 15 mL of CH2Cl2 and
the reaction quenched by addition of 10 mL of 5% NaHCO3 solution.
The product was extracted with 3 × 20 mL of CH2Cl2, and combined
JA974318B