Total synthesis of macquarimicins using an intramolecular Diels-Alder approach inspired by a biosynthetic pathway

Article abstract of DOI:10.1021/ja048320w

A total synthesis of the macquarimicins A-C (1-3), novel natural products with intriguing tetra- or pentacyclic frameworks, has been achieved. The synthesis features an extensive investigation of the biosynthesis-based intramolecular Diels-Alder (IMDA) re

Full text of DOI:10.1021/ja048320w

Published on Web 08/20/2004
Total Synthesis of Macquarimicins Using an Intramolecular
Diels-Alder Approach Inspired by a Biosynthetic Pathway
Ryosuke Munakata, Hironori Katakai, Tatsuo Ueki, Jun Kurosaka,
Ken-ichi Takao, and Kin-ichi Tadano*
Contribution from the Department of Applied Chemistry, Keio UniVersity,
Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Received March 24, 2004; E-mail: tadano@applc.keio.ac.jp
Abstract: A total synthesis of the macquarimicins A-C (1-3), novel natural products with intriguing tetra-
or pentacyclic frameworks, has been achieved. The synthesis features an extensive investigation of the
biosynthesis-based intramolecular Diels-Alder (IMDA) reactions of (E,Z,E)-1,6,8-nonatrienes. Considering
possible biosynthetic sequences, four types of substrates were synthesized, and their IMDA reactions were
examined. From one of the four substrates, the total synthesis was achieved via a transannular Diels-
Alder reaction, which led to the stereoselective construction of the unique molecular framework. The
convergent and efficient synthetic pathway afforded (+)-1 in 27 linear steps with 4.3% and 9.9% overall
yields from readily available ethyl (2E,4S)-4,5-(isopropylidene)dioxy-2-pentenoate (22) and (R)-epichloro-
hydrin (30), respectively. Furthermore, efficient syntheses of 2, 3, and the 9-epi-cochleamycins A (57) and
B (58) were accomplished. Additionally, the present work established the absolute stereochemistry of
macquarimicins and revised the C(2)-C(3) geometry of 1.
Introduction
Background. The macquarimicins A-C (1-3, Figure 1)
were isolated from Micromonospora chalcea by researchers at
Abbott Laboratories in 1995.1,2 Their planer structures and
relative stereochemistry except for C(14) of 3 were elucidated
on the basis of 1D- and 2D-NMR experiments and X-ray
crystallography of 2. The molecular architecture of macquar-
imicins is characterized by unique tetra- and pentacyclic
frameworks, which share a cis-tetrahydroindanone ring (AB
ring) and a â-keto-δ-lactone ring (D ring). Additionally,
macquarimicin A (1) and macquarimicin B (2) contain a strained
10-membered carbocycle (C ring) in which a conjugated alkene
is incorporated at the bridgehead position of the CD ring. On
the other hand, the pentacyclic framework of macquarimicin C
(3) contains a characteristic 2-oxabicyclo[2.2.2]octane substruc-
ture and an array of seven contiguous stereogenic centers,
including one quaternary carbon center.
Figure 1. Structures of macquarimicins A-C (1-3).
sphingomyelinase (N-SMase).3 Recently, N-SMase has been
emerging as an interesting pharmacological target, because
ceramide, an important second messenger produced by sphin-
gomyelinase, is involved in a variety of biological processes,
particularly inflammation and apoptosis.4 An improved under-
standing of SMase-dependent signaling may provide novel
strategies for the treatment of diseases such as inflammatory
and neurodegenerative diseases, as well as cancer. Thus,
selective inhibitors of N-SMase could be used to gain insight
into the enzyme mechanism, which is currently unknown, and
more importantly into the experimental therapy of such dis-
eases.5 In fact, the Sankyo researchers have shown that some
N-SMase inhibitors, including 1, inhibit LPS-induced production
Initially, macquarimicin A (1) was isolated as a very weak
antibacterial agent by the Abbott researchers, while macquar-
imicins B (2) and C (3) were found to exhibit cytotoxicity
against the P388 leukemia cell line (IC50 0.3 and 30.0 µg/mL,
respectively).1a In 1999, researchers at Sankyo Co. disclosed
that 1 is a selective inhibitor of membrane-bound neutral
(1) (a) Jackson, M.; Karwowski, J. P.; Theriault, R. J.; Rasmussen, R. R.;
Hensey, D. M.; Humphrey, P. E.; Swanson, S. J.; Barlow, G. J.;
Premachandran, U.; McAlpine, J. B. J. Antibiot. 1995, 48, 462-466. (b)
Hochlowski, J. E.; Mullally, M. M.; Henry, R.; Whittern, D. M.; McAlpine,
J. B. J. Antibiot. 1995, 48, 467-470.
(2) The structure of macquarimicin A was originally reported to be its (E)-
isomer concerning the C(2)-C(3) double bond. In this paper, however,
we use the structure 1 shown in Figure 1 because we found that the (Z)-
isomer 1 is the correct structure for macquarimicin A through this work.
See also ref 28.
(3) Tanaka, M.; Nara, F.; Yamasato, Y.; Masuda-Inoue, S.; Doi-Yoshioka, H.;
Kumakura, S.; Enokita, R.; Ogita, T. J. Antibiot. 1999, 52, 670-673.
(4) For applications of the N-SMase inhibitors, see: (a) Nara, F.; Tanaka, M.;
Hosoya, T.; Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 531-
535. (b) Wascholowski, V.; Giannis, A. Drug News Perspect. 2001, 14,
581-590. (c) Amtmann, E.; Baader, W.; Zoller, M. Drug Exp. Clin. Res.
2003, 29, 5-13.
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Total Synthesis of Macquarimicins
A R T I C L E S
been shown to catalyze Diels-Alder reactions in purified or
partially purified form. In 2003, the group of Tanaka and
Oikawa elucidated the structure of Diels-Alderase for the first
time by X-ray crystallography of MPS.15 In this area, synthetic
chemistry has been playing an important role. For example, the
catalytic activities on the Diels-Alder reactions of all three
enzymes were investigated using synthetically prepared sub-
strates. Details of the biosyntheses of 1-9 are still unclear.
Therefore, the development of a synthetic methodology may
help to elucidate the details by supplying synthetic probes. This
intriguing feature of this class of natural products, combined
with biological activities and a formidable molecular architec-
ture, makes them highly attractive targets for synthetic chemists.
In 1999, Sorensen and co-workers reported the first synthetic
study of FR182877 (8) and proposed the biosynthetic pathway
for the antibiotic.10 Soon after, synthetic investigations of 8 and
9 were reported by the groups of Armstrong,16 Sorensen,17
Nakada,18 Roush,19 and Clarke.20 In 2002, Sorensen and co-
workers21 and Evans and Starr22 independently achieved enan-
tioselective total syntheses of (+)- and (-)-8, respectively. Their
elegant approaches featured a domino sequence of two trans-
annular Diels-Alder (TADA) reactions that converted mono-
cyclic substrates into pentacyclic cycloadducts with remarkable
stereoselectivity.
The first report on the synthetic study of macquarimicins or
cochleamycins was disclosed by our group in 2001.23 Later,
the groups of Paquette24 and Roush25 also reported their
synthetic studies. All three studies concern the construction of
the tetrahydroindane ring (AB ring) using the IMDA reaction
of (E,Z,E)-1,6,8-nonatrienes as the key transformation. In 2003,
Tatsuta and co-workers26 disclosed the first total synthesis of
(+)-4 and established its absolute configuration. The Tatsuta
synthesis also features the IMDA reaction of an (E,Z,E)-triene
to form the AB ring, and they employed the SmI2-mediated
intramolecular Reformatsky reaction to construct the 10-
membered carbocycle. Very recently, the Roush group has also
accomplished their total synthesis of (+)-4 using a TADA
strategy.27 In 2003, we reported the first total synthesis of (+)-1
using a TADA reaction as the key step.28 Through this work,
we determined the absolute configuration of natural (+)-1 and
revised its proposed structure concerning the C(2)-C(3) ge-
ometry. Herein, we report a full account of the total synthesis
Figure 2. Structures of related natural products.
of IL-1â and PGE2, the key inflammatory cytokines, and exhibit
antiinflammatory activity in vivo by oral administration.3,4a
Closely related natural products, antitumor antibiotics, co-
chleamycin (4-7),6 a microtubule-stabilizing agent FR182877
(8),7,8 and hexacyclinic acid (9)9 have been isolated (Figure 2).
These natural products may share a biogenetic pathway that
involves the intramolecular Diels-Alder (IMDA) reaction of
polyketide intermediates.6d,10,11 It has been proposed that Diels-
Alder reactions may be involved in the biosynthesis of more
than 100 natural products.11b However, to date, only three natural
enzymes, solanapyrone synthase (SPS),12 lovastatin nonaketide
synthase (LNKS),13 and macrophomate synthase (MPS),14 have
(5) For examples of N-SMase inhibitors, see: (a) Nara, F.; Tanaka, M.; Hosoya,
T.; Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 525-530. (b)
Uchida, R.; Tomoda, H.; Dong, Y.; Omura, S. J. Antibiot. 1999, 52, 572-
574. (c) Tanaka, M.; Nara, F.; Yamasato, Y.; Ono, Y.; Ogita, T. J. Antibiot.
1999, 52, 827-830. (d) Uchida, R.; Tomoda, H.; Arai, M.; Omura, S. J.
Antibiot. 2001, 54, 882-889. (e) Arenz, C.; Giannis, A. Angew. Chem.,
Int. Ed. 2000, 35, 1440-1442. (f) Hakogi, T.; Monden, Y.; Iwama, S.;
Katsumura, S. Org. Lett. 2000, 2, 2627-2629. (g) Lindsey, C. C.; Go´mez-
D´ıaz, C.; Villalba, J. M.; Pettus, T. R. R. Tetrahedron 2002, 58, 4559-
4565.
(6) (a) Shindo, K.; Kawai, H. J. Antibiot. 1992, 45, 294-295. (b) Shindo, K.;
Matsuoka, M.; Kawai, H. J. Antibiot. 1996, 49, 241-243. (c) Shindo, K.;
Iijima, H.; Kawai, H. J. Antibiot. 1996, 49, 244-248. (d) Shindo, K.;
Sakakibara, M.; Kawai, H.; Seto, H. J. Antibiot. 1996, 49, 249-252.
(7) (a) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.; Hino,
M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123-130. (b) Sato,
B.; Nakajima, H.; Hori, Y.; Hino, M.; Hashimoto, S.; Terano, H. J. Antibiot.
2000, 53, 204-206. (c) Yoshimura, S.; Sato, B.; Kinoshita, T.; Takase, S.;
Terano, H. J. Antibiot. 2000, 53, 615-622; 2002, 55, C-1.
(8) Recently, carboxyesterase-1 inhibitory activity of 8 was reported: Adam,
G. C.; Vanderwal, C. D.; Sorensen, E. J.; Cravatt, B. F. Angew. Chem.,
Int. Ed. 2003, 42, 5480-5484.
(9) Ho¨fs, R.; Walker, M.; Zeeck, A. Angew. Chem., Int. Ed. 2000, 39, 3258-
3261.
(10) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Org. Lett.
1999, 1, 645-648. See also ref 21b.
(11) For reviews on the biosynthesis of Diels-Alder-type natural products,
see: (a) Ichihara, A.; Oikawa, H. Curr. Org. Chem. 1998, 2, 365-394.
(b) Ichihara, A.; Oikawa, H. In ComprehensiVe Natural Products Chemistry;
Sankawa, U., Ed.; Barton, D. H. R., Nakanishi, K., Meth-Cohn, O., Series
Eds.; Elsevier: Oxford, 1999; Vol. 1, pp 367-408. (c) Williams, R. M.;
Stocking, E. M. Angew. Chem., Int. Ed. 2003, 42, 3078-3115.
(12) Oikawa, H.; Kobayashi, T.; Katayama, K.; Suzuki, Y.; Ichihara, A. J. Org.
Chem. 1998, 63, 8748-8756.
(13) Auclair, K.; Sutherland, A.; Kennedy, J.; Witter, D. J.; Vanden Heever, J.
P.; Hutchinson, C. R.; Vederas, J. C. J. Am. Chem. Soc. 2000, 122, 11519-
11520.
(14) Watanabe, K.; Mie, T.; Ichihara, A.; Oikawa, H.; Honma, M. J. Biol. Chem.
2000, 275, 38393-38401.
(15) Ose, T.; Watanabe, K.; Mie, T.; Honma, M.; Watanabe, H.; Yao, M.;
Oikawa, H.; Tanaka, I. Nature 2003, 422, 185-189.
(16) Armstrong, A.; Goldberg, F. W.; Sandham, D. A. Tetrahedron Lett. 2001,
42, 4585-4587.
(17) Vanderwal, C. D.; Vosburg, D. A.; Sorensen, E. J. Org. Lett. 2001, 3, 4307-
4310.
(18) Suzuki, T.; Nakada, M. Tetrahedron Lett. 2002, 43, 3263-3267.
(19) Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5, 4223-4226.
(20) (a) Clarke, P. A.; Grist, M.; Ebden, M.; Wilson, C. Chem. Commun. 2003,
1560-1561. (b) Clarke, P. A.; Grist, M.; Ebden, M. Tetrahedron Lett. 2004,
45, 927-929.
(21) (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc.
2002, 124, 4552-4553. (b) The Sorensen group also has reported the total
synthesis of natural (-)-FR182877: Vanderwal, C. D.; Vosburg, D. A.;
Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393-5407.
(22) (a) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002, 41, 1787-
1790. (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531-
13540.
(23) Munakata, R.; Ueki, T.; Katakai, H.; Takao, K.; Tadano, K. Org. Lett.
2001, 3, 3029-3032.
(24) Chang, J.; Paquette, L. A. Org. Lett. 2002, 4, 253-256.
(25) Dineen, T. A.; Roush, W. R. Org. Lett. 2003, 5, 4725-4728.
(26) Tatsuta, K.; Narazaki, F.; Kashiki, N.; Yamamoto, J.; Nakano, S. J. Antibiot.
2003, 56, 584-590.
(27) Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043-2046.
(28) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.; Tadano, K.
J. Am. Chem. Soc. 2003, 125, 14722-14723.
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A R T I C L E S
Munakata et al.
Scheme 1. Plausible Biosynthetic Pathway of Macquarimicins
Scheme 2. Possible IMDA Reactions Forming a
cis-anti-cis-Tetrahydroindane
Table 1. Comparison of 1H NMR Data Reported for
Macquarimicin A to 4
b
c
positiona
macquarimicin A
cochleamycin A
of the macquarimicins A-C (1-3) by employing the biosyn-
thesis-based Diels-Alder strategy, in which the IMDA reactions
of a variety of (E,Z,E)-1,6,8-nonatrienes are extensively inves-
tigated. The present synthesis also features an efficient and
concise construction of the characteristic framework of mac-
quarimicins.
3
4
15
6.78 (d, 11.1)d
6.77 (d, 11.3)
3.44 (ddd, 11.1, 6.1, 2.4)
1.80 (dt, 15.4, 2.3)
2.49 (dddd, 15.4, 11.6, 4.7, 1.0)
2.67 (dd, 18.8, 0.8)
3.30 (ddd, 11.3, 5.6, 2.4)
1.78 (ddd, 15.5, 2.4, 2.4)
2.48 (ddd, 15.5, 11.8, 4.5)
2.66 (d, 19.0)
17
3.14 (ddd, 18.8, 7.4, 1.0)
3.11 (dd, 19.0, 7.5)
Biosynthetic Hypothesis. In 1996, Shindo, Seto, and co-
workers reported biosynthetic studies of cochleamycins using
13C- and 2H-labeled compounds, which revealed the polyketide
origin of cochleamycins and their carbon skeletons consisting
of eight acetate units and one propionate unit.6d In the study,
they proposed a biosynthetic hypothesis in which the sequential
IMDA reaction, the intramolecular Knoevenagel reaction, and
reductive transannular alkylation take place to form the molec-
ular architecture of cochleamycins. We supposed that 1 might
be synthesized through the common pathway to 4 (Scheme 1).
The order of the three cyclization reactions was unclear because
the isotope-labeling study6d indicates only a linear structure of
the polyketide precursor but not intermediates in the cyclization
sequence. A conjugate addition or a hetero Diels-Alder reaction
of an acetone equivalent to 1 followed by hydrolysis29 would
generate 2. A dehydrative transannular alkylation of 2 as
depicted would provide 3 with inversion of configuration.30 To
construct a tetrahydroindane ring with cis-anti-cis ring fusion
in an IMDA reaction, the reaction of an (E,Z,E)-1,6,8-nonatriene
has to proceed in endo-mode and the reaction of an (E,E,Z)-
1,6,8-nonatriene had to proceed in exo-mode (Scheme 2). With
these synthetic and stereochemical issues in mind, we embarked
on the synthesis of a variety of IMDA substrates.
a Macquarimicin numbering. b Cited from ref 1b. c Cited from ref 6c.
d Coupling constants in J ) Hz.
Figure 3. The most stable conformers for the C(2)-C(3) geometrical
isomers of macquarimicin A.
evidence. As shown in Table 1, the reported 1H NMR data for
macquarimicin A and cochleamycin A (4) are in substantial
agreement despite the opposite geometry at C(2)-C(3). On the
other hand, a molecular modeling study suggested the significant
conformational difference between each most stable conformer
for the two geometrical isomers (Figure 3).31 Thus, it might be
considered that macquarimicin A has the same C(2)-C(3)
geometry as that of 4, the geometry of which was determined
unambiguously by NOE experiments.32,33
Results and Discussion
Synthetic Plan. As mentioned in ref 2, we assumed mac-
quarimicin A has a C(2)-C(3) geometry opposite to that
reported in the original literature.1b The following is our
The retrosynthetic analysis of macquarimicins (1-3) is
outlined in Scheme 3. The core of our strategy was the
(29) Involvements of intermolecular hetero Diels-Alder reactions are suggested
in biosyntheses of several natural products: (a) Seo, S.; Sankawa, U.;
Ogihara, Y.; Itaka, Y.; Shibata, S. Tetrahedron 1973, 29, 3721-3726. (b)
Baldwin, J. E.; Mayweg, A. V. W.; Neumann, K.; Pritchard, G. J. Org.
Lett. 1999, 1, 1933-1935. (c) Adlington, R. M.; Baldwin, J. E.; Pritchard,
G. J.; Williams, A. J.; Watkin, D. J. Org. Lett. 1999, 1, 1937-1939.
(30) Although the configuration of C(14) in 3 had not been determined, it was
estimated to be the same as that of cochleamycin B (6).
(31) This calculation was performed with Spartan ’02 for Windows.
(32) In 1992, Shindo and co-workers reported the structure of 4 to be its E-isomer
(ref 6a), but they corrected it to the Z-isomer in a later report (ref 6c) based
on a 13C-{1H} NOE experiment.
(33) Although the Shindo group and ours depicted the structure of macquarimicin
A as its correct (Z)-isomer 1 (refs 6b and 23, respectively), the first mention
of this geometry issue was made by the Sorensen group (ref 21b).
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Total Synthesis of Macquarimicins
A R T I C L E S
Scheme 3. Retrosynthetic Analysis of Macquarimicins
construction of the molecular framework using the IMDA
reaction inspired by the proposed plausible biosynthesis.34-36
We employed this [4+2] cycloaddition strategy because we were
greatly interested in the possibility that the IMDA reaction of
(E,Z,E)-1,6,8-nonatrienes could be involved in the biosynthesis
of 1. This type of IMDA reaction has been far less utilized in
organic synthesis as compared to its (E,E,E)- and (Z,E,E)-
counterparts due to its lower rate and possible side reactions
such as olefin isomerization.37,38 We anticipated that this study
would help to enlarge the scope of this type of IMDA reaction,
which had not been fully investigated.
disclose the intrinsic reactivity of these natural products to verify
the proposed biosynthesis. Planning the synthesis of 1 featured
by the biomimetic Diels-Alder reaction, we were not sure of
the best structure of the substrate, due to the uncertain order of
the three ring-forming reactions. We planned to synthesize four
types of (E,Z,E)-substrates (14-17), considering possible cy-
clization sequences, to fully investigate the stereochemical
outcome of the IMDA reactions. The IMDA reactions of the
linear substrates 14 (path A) and 15 (path B) would provide
cycloadducts 10 and 11, respectively, bearing a â-ketoester or
a â-keto-δ-lactone moiety as a nucleophilic part for the
subsequent intramolecular Knoevenagel condensation. On the
other hand, the IMDA reactions of 16 (path C) and 17 (path
D), categorized as transannular Diels-Alder (TADA) reactions,
would produce 12 and 13, respectively, forming the 10-
membered carbocycle simultaneously.39,40 The cycloadduct 12
was expected to afford 1 by a δ-lactone formation, while the
cycloadduct 13 already possesses the tetracyclic framework of
1. These TADA approaches were especially of interest because
no biomimetic total synthesis employing the TADA approach
had been disclosed when we started this synthetic work.41,42
For the synthesis of these four types of IMDA substrates (14-
17), we designed a convergent and flexible strategy to carry
out the work efficiently (Scheme 4). First, the substrates (14-
17) were dissected at C(10)-C(11). This sp2-sp2 bond con-
nection would be realized by the Stille coupling reaction between
On the basis of the biosynthetic hypothesis shown in Scheme
1, we considered macquarimicin A (1) to be a precursor of 2
and 3 (Scheme 3). We were especially interested in the
stereochemical outcome of these transformations, which could
(34) For recent reviews on biomimetic syntheses, see: (a) Williams, R. M.;
Cox, R. Acc. Chem. Res. 2003, 36, 127-139. (b) Nicolaou, K. C.;
Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551-564. (c)
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Yang, J. J. Org. Chem. 1995, 60, 5785-5789. (b) Layton, M. E.; Morales,
C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773-775. (c) Germain,
J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269-5278. (d) Bodwell,
G. J.; Li, J. Angew. Chem., Int. Ed. 2002, 41, 3261-3262. (e) Soucy, P.;
L’Heureux, A.; Toro´, A.; Deslongchamps, P. J. Org. Chem. 2003, 68,
9983-9987. (f) Suzuki, T.; Usui, K.; Miyake, Y.; Namikoshi, M.; Nakada,
M. Org. Lett. 2004, 6, 553-556.
(38) For alkene isomerization of (E,Z)-1,3-dienes, see: (a) Matikainen, J.; Kalita,
S.; Ha¨ma¨la¨inen, M.; Hase, T. Tetrahedron 1997, 53, 4531-4538. (b)
Diedrich, M. K.; Kla¨rner, F.-G. J. Am. Chem. Soc. 1998, 120, 6212-6218.
(c) Allen, A.; Gordon, D. M. Indian J. Chem., Sect. B 1999, 38B, 269-
273.
(42) To date, four TADA-based biomimetic total syntheses have been reported
by the groups of Shair (ref 41b), Sorensen (ref 21), Evans (ref 22), and
Deslongchamps (ref 41e).
9
J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004 11257

A R T I C L E S
Munakata et al.
Scheme 4. Retrosynthetic Analysis of the IMDA Substrates
Scheme 5. Synthesis of (Z)-Stannylalkene 18
intermediates 18 and 19 or 20. The iodoalkenes 19 and 20 would
be, in turn, derived from 21. This strategy seemed to be
profitable for us because both 18 and 21 would serve as common
precursors for all four types of IMDA substrates. As the absolute
stereochemistry of the macquarimicins had not been established,
we started from readily available enantiopure starting materials
to synthesize 18 and 21, hopeful that our choice would
ultimately correspond to the absolute stereochemistry of the
target.
Synthesis of the Coupling Substrates. The coupling sub-
strate 18 was synthesized from known R,â-unsaturated ester 22,
which is readily available from D-mannitol43 (Scheme 5). The
diastereoselective conjugate addition of a methyl nucleophile
to 22 was conducted as reported by Leonard and co-workers.44
Thus, 22 was exposed to MeLi in diethyl ether at -78 °C to
give syn-adduct 23 as a single diastereomer. The ester group in
23 was reduced with LiAlH4, followed by Dess-Martin
oxidation45 and Horner-Wadsworth-Emmons olefination, pro-
viding (E)-unsaturated ester 24 with higher than 20:1 E-
selectivity. Reduction of 24 with diisobutylaluminum hydride
(Dibal-H) and deprotection of the acetonide gave triol 25. The
secondary hydroxyl group in 25 was selectively protected to
provide the (4-methoxyphenyl)methyl (MPM) ether 26 by diol
protection of 25 as the 4-methoxybenzylidene acetal,46 followed
by regioselective reductive cleavage of the acetal with Dibal-
H.47 The less-hindered allylic alcohol in 26 was selectively
protected as a tert-butyldiphenylsilyl (TBDPS) ether to afford
27 in 73% yield, with 13% of recovered 26. Dess-Martin
oxidation of 27 and subjection of the resultant aldehyde to
Corey-Fuchs conditions48 provided dibromoalkene 28. The
application of Uenishi’s method49 to 28 afforded (Z)-bromo-
alkene 29 exclusively.50 The halogen-lithium exchange of 29,
followed by treatment with Bu3SnCl, produced (Z)-stannylalkene
18.
The synthesis of the other coupling substrates 19 and 20
started from (R)-epichlorohydrin (30) via known acetylenic
compound 3151 (Scheme 6). The conversion of 31 to aldehyde
32 was conducted in a straightforward manner and proceeded
in an overall yield of 84% from 30.52 The BF3‚OEt2-mediated
vinylogous Mukaiyama aldol reaction between 32 and 33,53
prepared from 2,2,6-trimethyl-1,3-dioxin-4-one, proceeded
smoothly to give a 1:1 diastereomeric mixture of the adducts,
which was converted into â-hydroxyketone 34 in two additional
steps. The diastereoselective carbonyl reduction of 34, according
to Prasad’s procedure,54 gave the desired syn-1,3-diol 21
exclusively.55 From the common intermediate 21, the coupling
substrates 19 and 20 were synthesized as follows. Protection
of the two hydroxyl groups in 21 and conversion of the resultant
disilylated product to bromoalkyne 35, followed by one-pot
(50) The Wittig reaction of aldehyde derived from 27 using Ph3PCH2I2 and
NaHMDS as base gave a mixture of Z/E iodoalkene (ca. 5:1). See: Stork,
G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(51) Takano, S.; Kamikubo, T.; Sugihara, T.; Suzuki, M.; Ogasawara, K.
Tetrahedron: Asymmetry 1993, 4, 201-204.
(43) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis 1986,
403-406.
(44) Leonard, J.; Mohialdin, S.; Reed, D.; Ryan, G.; Swain, P. A. Tetrahedron
1995, 51, 12843-12858.
(52) In the reaction of 31 with KCN to form the corresponding nitrile, the use
of aqueous DMSO, instead of dry DMSO, prevented the formation of the
TMS ether, which was generated as a result of migration of the alkynyl
TMS group to the secondary alcohol.
(45) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287. (c)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (d) Frigerio, M.;
Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
(46) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984, 2371-
2374.
(53) Grunwell, J. R.; Karapides, A.; Wigal, C. T.; Heinzman, S. W.; Parlow, J.;
Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens, J. E. J. Org.
Chem. 1991, 56, 91-95.
(54) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155-158.
(47) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593-
(55) The syn-stereochemistry of 21 was confirmed on the basis of 13C NMR
chemical shifts of the corresponding 1,3-diol acetonide using the well-
recognized empirical rule of Rychnovsky et al.: Rychnovsky, S. D.; Rogers,
B.; Yang, G. J. Org. Chem. 1993, 58, 3511-3515. See Supporting
Information for details.
1596.
(48) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(49) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998,
63, 8965-8975.
9
11258 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004

Total Synthesis of Macquarimicins
A R T I C L E S
as MOM enol ether (not shown) at -18 °C.61 We also searched
for deprotection conditions for the resultant MOM enol ether
and found that treatment with MgBr2‚OEt2 and EtSH in Et2O
at room temperature cleanly regenerated the starting â-keto-δ-
lactone.62 For example, the MOM group in the coupling
substrate 20 was deprotected under these conditions in 98%
yield. The present protection/deprotection methodology will
enhance the synthetic flexibility for compounds involving
â-keto-δ-lactones, which are frequently utilized as intermediates
in natural product synthesis63 and medicinal chemistry,64 as in
the synthesis of HIV protease inhibitor tipranavir.64b
Scheme 6. Synthesis of the (E)-Iodoalkenes 19 and 20
Stille Coupling. With stannane 18 and iodides 19 and 20 in
hand, we examined the Stille coupling reaction to combine
them.65 To probe the viability of the reaction, we conducted a
preliminary study using several compounds related to 18 with
the TBS ether of (E)-4-iodo-3-propen-1-ol or (E)-4-tributyl-
stannyl-3-propen-1-ol as a coupling partner (Scheme 7). The
results on the Stille coupling reactions using (Z)-bromoalkenes
or -iodoalkenes, carrying an aldehyde or a hydroxymethyl group
(59) Although a number of â-keto-δ-lactone equivalents have been synthesized,
studies in the context of protection/deprotection have not been reported.
See: (a) Nakata, T.; Takao, S.; Fukui, M.; Tanaka, T.; Oishi, T. Tetrahedron
Lett. 1983, 24, 3873-3876. (b) Dziadulewicz, E.; Giles, M.; Moss, W. O.;
Gallagher, T.; Harman, M.; Hursthouse, M. B. J. Chem. Soc., Perkin Trans.
1 1989, 1793-1798. (c) D’Angelo, J.; Gomez-Pardo, D. Tetrahedron Lett.
1991, 32, 3063-3066. (d) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee,
V. J. J. Am. Chem. Soc. 2000, 122, 10033-10046. (e) Branda¨nge, S.;
Fa¨rnba¨ck, M.; Leijonmarck, H.; Sundin, A. J. Am. Chem. Soc. 2003, 125,
11942-11955.
(60) Other protecting groups such as TBS, pivaloyl, and Boc were found to be
too labile, while the N,N-dimethylcarbamoyl and 2,4,6-trimethylbenzoyl
(mesitoyl) groups were too robust. The difficulty in enol-type protections
arises from the vinylogous carbonate substructure making protecting groups
labile and the â-acyloxyketone substructure leading to an easy elimination
reaction. Ketal-type protecting groups such as dithiolane or dioxolane were
also examined, but the protection and/or deprotection were less efficient.
(61) Neither MOM etherification of the secondary alcohol nor C-alkylation at
the R-position of the â-keto-δ-lactone was observed under these conditions.
(62) Without EtSH, the scavenger for forming the formaldehyde equivalent, the
yield of the deprotection dropped significantly due to the formation of a
methylene-tethered dimer via the Knoevenagel-Michael reaction sequence
shown below.
hydrostannylation-iodination,56 afforded (E)-iodoalkene 19. On
the other hand, treatment of 21 under modified Sato and
Kaneko’s conditions reported by Carreira57 gave a transient
â-keto-δ-lactone, in which the keto carbonyl and the hydroxyl
group were protected as a methoxymethyl enol ether and as a
TBS ether, respectively, to produce 36 efficiently. Hydrostan-
nylation of 36 under radical conditions using AIBN as an
initiator and subsequent treatment of the resultant (E)-stannyl-
alkene with I2 produced the (E)-iodoalkene 20.
In our earlier synthetic work conducted using compounds with
the â-keto-δ-lactone structure, protection of the keto carbonyl
was required due to the highly acidic and reactive nature of
cyclic 1,3-dicarbonyl compounds.58 To the best of our knowl-
edge, no practical procedure for the protection of â-keto-δ-
lactone has been reported.59 We conducted a search to seek the
most suitable protecting group for our case and found a
methoxymethyl (MOM) group to be the best choice.60 Therefore,
the â-keto-δ-lactone generated from 21 was selectively protected
(63) (a) Ohmori, K.; Suzuki, T.; Miyazawa, K.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1993, 34, 4981-4984. (b) Spino, C.; Mayes, N.;
Desfosses, H.; Sotheeswaran, S. Tetrahedron Lett. 1996, 37, 6503-6506.
(c) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Farrugia, L. J.;
Muir, K.; Boyle, F. T. J. Chem. Soc., Perkin Trans. 1 2000, 2357-2384.
(d) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749-3754.
(64) (a) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton,
R. S. J. Med. Chem. 1990, 33, 31-38. (b) Turner, S. R.; Strohbach, J. W.;
Tommasi, R. A.; Aristoff, P. A.; Johnson, P. D.; Skulnick, H. I.; Dolak, L.
A.; Seest, E. P.; Tomich, P. K.; Bohanon, M. J.; Horng, M.-M.; Lynn, J.
C.; Chong, K.-T.; Hinshaw, R. R.; Watenpaugh, K. D.; Janakiraman, M.
N.; Thaisrivongs, S. J. Med. Chem. 1998, 41, 3467-3476. (c) Boyer, F.
E.; Vara Prasad, J. V. N.; Domagala, J. M.; Ellsworth, E. L.; Gajda, C.;
Hagen, S. E.; Markoski, L. J.; Tait, B. D.; Lunney, E. A.; Palovsky, A.;
Ferguson, D.; Graham, N.; Holler, T.; Hupe, D.; Nouhan, C.; Tummino,
P. J.; Urumov, A.; Zeikus, E.; Zeikus, G.; Gracheck, S. J.; Sanders, J. M.;
VanderRoest, S.; Brodfuehrer, J.; Iyer, K.; Sinz, M.; Gulnik, S. V.; Erickson,
J. W. J. Med. Chem. 2000, 43, 843-858.
(56) For hydrostannylation of 1-bromoalkynes, see: Boden, C. D. J.; Pattenden,
G.; Ye, T. J. Chem. Soc., Perkin Trans. 1 1996, 2417-2419.
(57) (a) Sato, M.; Sakai, J.; Sugita, Y.; Yasuda, S.; Sakoda, H.; Kaneko, C.
Tetrahedron 1991, 47, 5689-5708. (b) Singer, R. A.; Carreira, E. M. J.
Am. Chem. Soc. 1995, 117, 12360-12361.
(58) For example, the acidity of δ,δ-dimethyl-â-keto-δ-lactone (2,2-dimeth-
ylpyran-4,6-dione, pKa ) 10.5) is between those of Meldrum’s acid (pKa
) 7.3) and dimedone (pKa ) 11.2) in DMSO, which is stronger than acetic
acid (pKa ) 12.3). The pKa values are cited from the following references:
(a) Arnett, E. M.; Harrelson, J. A., Jr. J. Am. Chem. Soc. 1987, 109, 809-
812. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(65) For reviews of the Stille coupling reaction, see: (a) Stille, J. K. Pure Appl.
Chem. 1985, 57, 1771-1780. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508-524. (c) Mitchell, T. N. Synthesis 1992, 803-815. (d) Farina,
V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1-652. (e)
Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999,
1235-1246.
9
J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004 11259

A R T I C L E S
Munakata et al.
Scheme 7. Mizorogi-Heck-type Cyclization of (Z)-Alkene
Derivatives
Scheme 8. Model IMDA Studies with (E,Z,E)- and
(E,E,Z)-1,6,8-Nonatrienes 38 and 39
Table 2. Optimization of the Conditions for the Stille Coupling
Reaction of 18 and 19a
catalyst. We found that the use of Pd(PPh3)4 reduces undesired
byproducts to provide a 72% yield of 37 (entry 6).70 After
optimization of the catalyst loading, we finally found that the
optimal conditions involve the use of a smaller amount (6 mol
%) of Pd(PPh3)4 in THF with the slow addition to the mixture
of 18, 19, and CuCl in DMSO-THF. The coupling reaction
proceeded reproducibly to provide 37 in 97% (entry 7).71
The Intramolecular Diels-Alder (IMDA) Reactions. After
optimizing the Stille coupling conditions, we investigated the
key IMDA reaction. Prior to carrying out the IMDA reactions
of 14-17, we conducted a study using a model substrate 38,
which possesses the same substitution pattern on C(7) and C(8)
as that in 14-17, to test the reactivity of (E,Z,E)-1,6,8-nonatriene
(Scheme 8).23 In addition, we conducted the IMDA reaction of
(E,E,Z)-1,6,8-nonatriene 39, another candidate involved in the
proposed biosynthesis of the macquarimicins and cochleamycins6b
(Schemes 1 and 2). There have been no reports to date
concerning the construction of a tetrahydroindane ring by the
IMDA reaction of (E,E,Z)-1,6,8-nonatriene.
entry
catalyst
CuX
CuI
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
solvent
yield (%)b
1
2
3
4
5
6
7c
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd(PPh3)4
DMF
DMF
DMF
14
30
34
59
70
72
97
DMSO
DMSO-THF (1:1)
DMSO-THF (1:1)
DMSO-THF (1:1)
Pd(PPh3)4
a Reactions were conducted using 10 mol % of Pd catalyst and 1 equiv
of CuX unless otherwise noted. b The yield from 19. c 6 mol % of Pd catalyst
was used.
as the left-hand terminal, were unsatisfactory due to the
predominant occurrence of an intramolecular Mizorogi-Heck-
type cyclization to give cyclohexene derivatives through the
mechanism shown. Furthermore, an O-unprotected (Z)-stannyl-
alkene and an O-TBDPS-protected (Z)-haloalkene again gave
the corresponding cyclohexene derivatives as the predominant
product.66 Consequently, the use of a left-hand-protected (Z)-
stannylalkene such as 18 was inevitable. Establishing 18 as the
optimal substrate, we explored the Stille coupling reaction of
18 and 19.
The results of the targeted Stille coupling are shown in Table
2. First, we examined standard conditions using 10 mol % of
PdCl2(MeCN)2 and a stoichiometric amount of cuprous halide
in DMF (entries 1-3).67,68 The reaction was promoted most
effectively with CuCl (entry 3), although the yield was still
insufficient (34%). The reaction rate increased in the following
order: CuI < CuBr < CuCl. Establishing CuCl as the optimal
promoter, we next examined the effect of reaction solvents.
Substantial improvement was achieved by using DMSO (59%,
entry 4), and a further increase in yield was accomplished using
a 1:1 DMSO-THF mixed solvent system (entry 5), which
afforded a 70% yield of 37.69 We then optimized the palladium
The IMDA reaction of (E,Z,E)-triene 3872 proceeded at 150
°C (5 h) in the presence of BHT (2,6-di-tert-butyl-4-methyl-
phenol) in a sealed tube to afford the desired cycloadduct 40 in
75% yield with a selectivity of >20:1.73,74 In this reaction,
isomerization of the diene moiety was not observed. On the
other hand, the IMDA reaction of (E,E,Z)-triene 3972 did not
(70) The substantial byproduct was a dimeric (E,Z)-diene generated from 19.
The corresponding (E,E)-diene was not observed. Stereospecific formation
of the (E,Z)-dimer can be explained by an intermolecular Mizorogi-Heck-
type mechanism, which involves three elemental steps as shown below:
(1) oxidative addition of 19 to Pd(0), (2) insertion of another molecule of
19, and (3) the syn elimination of â-iodide, instead of the usual â-hydride,
to give the dimeric (E,Z)-diene. For examples of similar reactions involving
â-bromide elimination, see: (a) Grigg, R.; Stevenson, P.; Worakun, T.
Tetrahedron 1988, 44, 2049-2054. (b) Edvardsen, K. R.; Benneche, T.;
Tius, M. A. J. Org. Chem. 2000, 65, 3085-3089.
(66) Recently a Mizorogi-Heck-type reaction using organostannanes was
reported: Hirabayashi, K.; Ando, J.; Kawashima, J.; Nishihara, Y.; Mori,
A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 1409-1417.
(67) Conditions using a palladium catalyst solely did not afford the desired
product 37, presumably due to a slow transmetalation step caused by steric
hindrance around the stannylalkene part in 18. Also, the stoichiometric
amount of CuCl was essential to promote the reaction effectively.
(68) For discussions on the copper effect in the Stille reaction, see: (a)
Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364. (b)
Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org.
Chem. 1994, 59, 5905-5911. (c) Casado, A.; Espinet, P. Organometallics
2003, 22, 1305-1309.
(71) Corey et al. have reported the utility of the CuCl/LiCl/Pd(PPh3)4/DMSO
system in Stille coupling: Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem.
Soc. 1999, 121, 7600-7605.
(72) For the syntheses of model substrates 38 and 39, see the Supporting
Information.
(73) The diastereomers of 40 were not found.
(74) The stereochemistry of the predominant product was unambiguously
determined by analysis of the 1H NMR spectrum and NOE experiments.
For details, see the Supporting Information.
(69) We examined the DMSO-THF mixed solvent due to the low solubility of
substrates to DMSO alone.
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11260 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004

Total Synthesis of Macquarimicins
A R T I C L E S
Figure 4. Plausible mechanism for the stereoselectivity in the IMDA
reaction of 38.
take place at 150 °C but proceeded slowly at 185 °C (11 days).
This reaction produced a mixture of six cycloadducts in a ratio
of 1:1:1:0.1:0.1:0.1.75 One of the three major cycloadducts
proved to be identical to the cycloadduct 40, which might have
been generated via an exo transition state. Theoretically, the
IMDA reaction of (E,E,Z)-triene 39 provides four cycloadducts
at most when the reaction proceeds concertedly, as is usually
accepted. Therefore, alkene isomerization of 39 was probably
involved in the formation of the other two cycloadducts.76
The stereochemical result from the IMDA reaction of 38 is
rationalized by considering the two transition states illustrated
in Figure 4. As it is generally accepted that exo transition states
are unlikely to be accessible because the reaction sites do not
approach each other closely enough to react in the IMDA
reaction of a (E,Z,E)-nonatriene, only two endo transition states,
TS-A or TS-B, are possible. As compared with TS-B, TS-A
leading to 40 seems to be substantially more favorable because
a severe steric interaction between the (4-methoxyphenyl)-
methoxy group and vinylic hydrogen exists in TS-B. Conse-
quently, the configuration at C(8) attaching the OMPM group
should significantly affect the π-facial selection of the cycload-
dition.77 By comparison of the result obtained from the IMDA
of 38 with Paquette’s observation,24,78 it is obvious that the
diastereocontrol induced by the C(8)-substituent is superior to
that by the C(7)-substituent. Meanwhile, the effect of substit-
uents at C(6) and C(7) (macquarimicin numbering) on stereo-
selectivity in the IMDA reaction of (E,Z,E)-1,6,8-nonatrienes
Figure 5. Transition structures for the IMDA reaction of (E,Z,E)- and
(E,E,Z)-undecatrienals. Units are in Å (length) or deg (angle). Atom numbers
correspond to those of macquarimicins.
has not been investigated systematically. Further investigations
are required for a more precise account of the diastereoselectivity
to enhance the synthetic value of the IMDA reaction of (E,Z,E)-
1,6,8-nonatrienes.
To synthesize a tetrahydroindane framework with cis-anti-
cis ring fusion, the results depicted in Scheme 8 imply that
(E,Z,E)-nonatrienes are apparently more useful than (E,E,Z)-
nonatrienes in regard to both reactivity and stereoselectivity.
To obtain a deep insight into the origin of the observed
significant reactivity difference, transition structures (TSs) of
the IMDA reactions of (E,Z,E)- and (E,E,Z)-undecatrienal have
been theoretically studied by means of DFT (B3LYP) calcula-
tions (Figure 5).31,79
(75) The ratio was determined by 1H NMR analysis taken for partly purified
mixtures of the cycloadducts.
(76) Two types of isomerization reactions, E/Z isomerization and a [1,5]-
hydrogen shift, are probably involved. The former generates an (E,E,E)-
1,6,8-nonatriene to give diastereomeric tetrahydroindanes, while the latter
generates an (E,Z,E)-1,7,9-decatriene to give octahydronaphthalenes. The
combination of the two isomerization processes, which produces an (E,E,E)-
1,7,9-decatriene, is also possible.
Electronic energies of transition structures relative to ground
states were calculated to be 30.6, 34.1, and 33.1 kcal/mol for
(E,Z,E)-endo, (E,E,Z)-endo, and (E,E,Z)-exo TS, respectively.80
The lower activation barrier for the (E,Z,E)-undecatrienal agrees
with experimentally observed higher reactivity of (E,Z,E)-triene
38 as compared with the (E,E,Z)-isomer 39. On the basis of
transition structures shown in Figure 5, we consider that the
(77) For previous discussions on this diastereoselectivity, see ref 37d-f.
(78) Chang and Paquette (ref 24) reported the result shown below. In their study,
the formation of another diastereomer was not observed.
(79) The calculation was carried out using the B3LYP/6-31G(d) level of theory.
Vibrational frequency calculations were carried out to ensure the authenticity
of the transition structures. The vibration associated with the imaginary
frequency was checked to correspond with a movement in the direction of
the reaction coordinate.
(80) Energies include zero-point energy corrections.
9
J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004 11261

A R T I C L E S
Munakata et al.
Scheme 9. Intramolecular Diels-Alder Reaction of 14
lower reactivity of (E,E,Z)-triene 39 is predominantly attributable
to steric interactions. A nonbonding interaction between H(8)-
H(12) [for the (E,Z,E)-isomer] or H(9)-H(13) [for the (E,E,Z)-
isomer] exists because of the s-cis conformation of the (E,Z)-
diene, which makes the distance between two hydrogen atoms
shorter than the sum of van der Waals radii (2.4 Å). This is
most prominent in the case of the (E,E,Z)-endo TS. In the
(E,E,Z)-exo TS, the repulsion is somewhat released by rotation
around C(12)-C(13), which is not available in the (E,E,Z)-endo
TS due to another steric interaction between H(4)-H(13). The
longer H(8)-H(12) distance in the (E,Z,E)-endo TS reduces the
steric repulsion, making it the most favorable transition state.
An additional nonbonding interaction exists in the (E,E,Z)-exo
TS between H(13) and the C(3) carbonyl oxygen. In this case,
the distance between the two atoms (2.16 Å) is remarkably
shorter than the sum of van der Waals radii (2.6 Å).81 Strains
in the forming cyclopentane ring do not seem to be the
determining factor because Newman projections of a C(5)-
C(9)-forming bond suggest a twist-mode asynchronicity82,83 of
(E,E,Z)-TSs similar to that of (E,E,E)-counterparts.84 For
example, Roush and co-workers reported two examples of
IMDA reactions in which (E,E,E)-1,6,8-nonatrienes possessing
a similar substitution pattern to 39 reacted at 85 and 110 °C.85
Considering the above discussions together, the reactivity
difference between 38 and 39 seems to originate from the steric
repulsions in the transition states, although further experimenta-
tion is required to confirm the generality of the reactivity order.
Confirming the feasibility of the IMDA reaction using
(E,Z,E)-trienes, we advanced to the IMDA substrates 14-17.
The case of 14, the IMDA substrate in path A (Scheme 3), is
depicted in Scheme 9. The Stille coupling product 37 was treated
with ammonium fluoride in MeOH86 to remove the TBDPS
group selectively. The resultant primary alcohol 41 was oxidized
with MnO2 in CH2Cl2 to give R,â-unsaturated aldehyde 42.
Heating of 42 at 150 °C in 1-butanol in a sealed tube for 6 h
resulted in the formation of cycloadduct 1074 through the IMDA
reaction of transient 14, generated by thermolysis of the
dioxinone ring in 42 via a retro hetero Diels-Alder reaction.87
Although the yield of the cycloaddition was moderate (66%)
due to the instability of the â-ketoester moiety,88 the reaction
proceeded with a diastereoselectivity higher than 20:1.89
We next examined the IMDA reaction corresponding to path
B in Scheme 3. To synthesize the IMDA substrate 15, the Stille
coupling of (Z)-stannylalkene 18 and (E)-iodoalkene 20 was
undertaken (Scheme 10).90 Subsequent removal of the TBDPS
group in the coupling product and oxidation of the resultant
allylic alcohol 43 with MnO2 provided the IMDA substrate 15.
The IMDA reaction of 15 occurred at 150 °C, providing four
cycloadducts. The major cycloadduct was characterized to be
1174 (81%), and one of the other cycloadducts was found to be
diastereomer 4474 (6%). Interestingly, the other product proved
to be a mixture of hetero Diels-Alder cycloadducts 45 (9% as
a 3:2 mixture of diastereomers). Although a large number of
reports on the intramolecular hetero Diels-Alder reaction have
been reported,91 to the best of our knowledge, this is the first
example of the isolation of a hetero cycloadduct as a byproduct
in the “normal” IMDA reaction of 1,6,8-nonatrienes or 1,7,9-
decatrienes.
(81) Even though this interaction is absent in the s-trans conformation for the
(E,E,Z)-exo TS, the s-cis conformation was proved to have lower energy,
reflecting the general s-cis preference in the Diels-Alder reactions. For
example, in the Diels-Alder reaction of butadiene and acrolein, it is
reported that the s-cis conformation is preferred to the s-trans conformation
in either the endo or the exo transition state by 1.3 or 1.8 kcal mol-1
,
respectively (B3LYP/6-31G(d)): (a) Garc´ıa, J. I.; Mart´ınez-Merino, V.;
Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1998, 120, 2415-2420.
(b) Kong, S.; Evenseck J. D. J. Am. Chem. Soc. 2000, 122, 10418-10427.
(82) In the early 1980s, the importance of asynchronous transition states was
proposed for interpreting the endo-selectivity of the IMDA reactions of
(E,E,E)-nonatrienes: (a) Roush, W. R.; Peseckis, S. M. J. Am. Chem. Soc.
1981, 103, 6696-6704. (b) White, J. D.; Sheldon, B. G. J. Org. Chem.
1981, 46, 2273-2280. (c) Taber, D. F.; Campbell, C.; Gunn, B. P.; Chiu,
I.-C. Tetrahedron Lett. 1981, 22, 5141-5144.
We then investigated the behavior of the mixture 45 under
the same thermal conditions because this compound implies the
(83) Houk and Brown introduced the concept of the “twist-asynchronous” model,
in which a torque applied to the forming bond by the connecting chain
plays an important role: Brown, F. K.; Houk, K. N. Tetrahedron Lett.
1985, 26, 2297-2300. See also: (a) Lin, Y.-T.; Houk, K. N. Tetrahedron
Lett. 1985, 26, 2269-2272. (b) Wu, T.-C.; Houk, K. N. Tetrahedron Lett.
1985, 26, 2293-2296. (c) Lin, Y.-T.; Houk, K. N. Tetrahedron Lett. 1985,
26, 2517-2520.
(84) (a) Raimondi, L.; Brown, F. K.; Gonzalez, J.; Houk, K. N. J. Am. Chem.
Soc. 1992, 114, 4796-4804. (b) Brown, F. K.; Raimondi, L.; Houk, K.
N.; Bock, C. W. J. Org. Chem. 1992, 57, 4862-4869.
(85) (a) Roush, W. R.; Wada, C. K. J. Am. Chem. Soc. 1994, 116, 2151-2152.
(b) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S. Tetrahedron Lett. 1987,
28, 2447-2450.
(88) The major side reaction was the formation of a methyl ketone, resulting
from the loss of the butoxycarbonyl group in 10.
(89) A cycloadduct, likely to be a diastereomer, was also isolated in a smaller
amount of 2%. However, we were not able fully to characterize this minor
product due to the contamination of another byproduct, which was hardly
removed by silica gel chromatography.
(90) This reaction was conducted prior to the optimization of the Stille coupling
conditions.
(91) For some examples of the construction of the 5-6 bicyclic system by an
intramolecular hetero Diels-Alder reaction, see: (a) Schreiber, S. L.;
Meyers, H. B. J. Am. Chem. Soc. 1988, 110, 5198-5200. (b) Tietze, L. F.;
Denzer, H.; Hodgru¨n, X.; Neumann, M. Angew. Chem., Int. Ed. Engl. 1987,
26, 1295-1297. (c) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J.
Am. Chem. Soc. 1988, 110, 6467-6471. (d) Takano, S.; Ohkawa, T.;
Tamori, S.; Satoh, S.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1988,
189-191. (e) Tietze, L. F.; Brumby, T.; Pfeiffer, T. Liebigs Ann. Chem.
1988, 9-12. (f) Shrestha, K. S.; Honda, K.; Asami, M.; Inoue, S. Bull.
Chem. Soc. Jpn. 1999, 72, 73-83.
(86) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177-1180.
(87) (a) Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984, 49,
5105-5108. (b) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431-
2435. (c) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
12360-12361.
9
11262 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004

Total Synthesis of Macquarimicins
A R T I C L E S
Scheme 10. Intramolecular Diels-Alder Reaction of 15
the latter is unlikely to be the primary pathway of the former
reaction.
Next, we examined the IMDA reaction via path C in Scheme
3, the TADA of 16. In addition to the substrate 16, we prepared
another substrate 49, which bears MOM groups for the
protection of the 1,3-diol part (Scheme 11). Thus, the primary
alcohol 41 was converted into methyl carbonate 46. From 46,
the TADA substrates 16 and 49 were synthesized independently.
Thermolysis of 46 in the presence of MeOH afforded â-keto
ester 47a in nearly quantitative yield. Alternatively, two TBS
groups in 46 were removed with HF‚pyr., and the resultant diol
was protected as di-MOM ether. Thermolysis of this compound
as conducted for 46 gave another â-keto ester 47b. The Pd(0)-
catalyzed macrocyclization94,95 of allyl carbonate 47a or 47b
was successfully carried out to form the desired 17-membered
macrocycles 48a or 48b (both as ca. 3:2 diastereomeric
mixtures), respectively, using Pd(PPh3)4/dppe (1:1) as a cata-
lyst.96 Introduction of a conjugate double bond into 48a or 48b
was then successfully carried out by a phenylselenenylation-
oxidation sequence97,98 to give the TADA substrate 16 or 49,
respectively, with a high geometric ratio (>20:1) in favor of
the desired (Z)-isomer.74,99
The TADA reactions of 16 and 49 proceeded at 130 °C. In
contrast to the IMDA reactions of 14 and 15, both 16 and 49
gave mixtures of at least five cycloadducts without remarkable
stereoselectivity and in unpractical yields.100 As mentioned
above, theoretically, the (E,Z,E)-trienes only attain endo transi-
tion states affording two diastereomers. Thus, an alkene
isomerization or regioisomeric IMDA reaction must be involved
Table 3. Thermal Conversion of 45 to 11
1
in the TADA reactions of 16 and 49. Inspection of H NMR
spectra suggested that most of the cycloadducts possess newly
formed carbon-carbon bonds between C(4)-C(12) and C(5)-
C(9). Thus, the minor products probably arose from alkene
isomerization of the substrates. Although isolation and charac-
terization of all of the products were quite difficult, we were
able to elucidate the stereochemistry of the major cycloadducts
obtained in both TADA reactions. In the case of 16, the desired
cycloadduct 12 was not obtained. The diastereomer 51a74 and
ratioa
time (h)
45
15
11
0
9
34
60
100
87
43
0
8
3
4
0
5
54
77
(93) Burke and co-workers have reported a retro hetero IMDA/IMDA reaction
in an attempted Claisen rearrangement: Burke, S. D.; Armistead, D. M.;
Shankaran, K. Tetrahedron Lett. 1986, 27, 6295-6298.
(94) (a) Kitagawa, Y.; Itoh, A.; Hashimoto, S.; Yamamoto, H.; Nozaki, H. J.
Am. Chem. Soc. 1977, 99, 3864-3867. (b) Trost, B. M.; Verhoeven, T. R.
J. Am. Chem. Soc. 1977, 99, 3867-3868. (c) Trost, B. M.; Ohmori, M.;
Boyd, S. A.; Okawara, H.; Brickner, S. J. J. Am. Chem. Soc. 1989, 111,
8281-8284. (d) Review: Trost, B. M. AnVew. Chem., Int. Ed. Engl. 1989,
28, 1173-1192.
(95) For recent applications, see: (a) Reference 21. (b) Fu¨rstner, A.; Weintritt,
H. J. Am. Chem. Soc. 1998, 120, 2817-2825. (c) Hoffmann, H. M. R.;
Pohlmann, J. Tetrahedron Lett. 1998, 39, 7085-7088. (d) Fu¨rstner, A.;
Krause, H. J. Org. Chem. 1999, 64, 8281-8286. (e) Yuasa, H.; Makado,
G.; Fukuyama, Y. Tetrahedron Lett. 2003, 44, 6235-6239.
(96) The use of the corresponding acetate instead of the carbonate 47a also
afforded macrocycle 48a (Pd(PPh3)4, dppe, BSA, THF, reflux). However,
the yield was capricious (51-86%) due to the formation of a terminal diene,
which was formed via the â-hydride elimination of the intermediary
π-allylpalladium complex. For the use of carbonates in Pd-catalyzed allylic
alkylation, see: Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.;
Takahashi, K. J. Org. Chem. 1985, 50, 1523-1529.
19
a Determined by H NMR analysis of the reaction mixture.
1
possible involvement of the hetero IMDA/Claisen rearrangement
pathway92 in the conversion of 15 to 11 or 44 (Table 3). The
results shown in Table 3 suggest the direct formation of both
11 and 44 from 15 but not via 45. On heating of 45 at 150 °C,
formation of the cycloadduct 11 and the IMDA substrate 15
was indeed observed. Although 45 was a 3:2 diastereomeric
mixture, 11 was formed stereoselectively, and only a trace
amount of 44 was observed in the 1H NMR analysis of the crude
mixture. Considering the formation of 15 and the diastereo-
selectivity, it is reasonable to conclude that the conversion of
45 to 11 proceeds via the retro hetero IMDA/IMDA sequence
but not via Claisen rearrangement.93 Additionally, as the reaction
of 15 leading to 11 (8 h) is much faster than that of 45 to 11,
(97) In the selenenylation reaction, addition of PhSeCl as a toluene solution,
not a THF solution, was essential for maintaining reproducibility.
(98) Although the intermediary selenide was a diastereomeric mixture (ca. 2:1),
virtually one geometrical isomer was formed through the oxidation/syn-
elimination process.
(92) For examples of Claisen rearrangement in related systems, see: (a) Bu¨chi,
G.; Powell, J. E., Jr. J. Am. Chem. Soc. 1970, 92, 3126-3133. (b) Ireland,
R. E.; Godfrey, J. D.; Thaisrivongs, S. J. Am. Chem. Soc. 1981, 103, 2446-
2448. (c) Childers, W. E., Jr.; Pinnick, H. W. J. Org. Chem. 1984, 49,
5277-5279. (d) Turos, E.; Audia, J. E.; Danishefsky, S. J. J. Am. Chem.
Soc. 1989, 111, 8231-8236. (e) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org.
Lett. 2002, 4, 1343-1345.
(99) We explored the synthesis of 16 from the aforementioned linear R,â-
unsaturated aldehyde 14 in a more straightforward manner by employing
the intramolecular Knoevenagel reaction. However, the desired 17-
membered carbocycle was not obtained despite extensive exploration.
(100) In addition to 16 and 49, we also examined a TADA substrate without
protecting groups for the 1,3-diol moiety. However, the TADA substrate
in this case decomposed under the thermal conditions (150 °C).
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A R T I C L E S
Munakata et al.
Scheme 11. Synthesis and Transannular Diels-Alder Reaction of 16 and 49a
a (a) Not observed. (b) A small amount (<10%) of these products might be generated.
Scheme 12. Transannular Diels-Alder Reaction of 17
geometrical isomer 52a74 were isolated as the major products.
On the other hand, the TADA reaction of the MOM-protected
substrate 49 provided the desired 5074 as the major product
despite a low yield of 29%. Small amounts of isomeric
cycloadducts, presumably 51b and 52b, were formed, although
we were not able to isolate them in pure form.
The unsuccessful results obtained from the TADA reactions
using the substrates 16 and 49 are considered to be attributable
to easy alkene isomerization. Regarding the TADA substrates
16 and 49, their macrocyclic structure seems to accelerate
undesired side reactions such as alkene isomerization. In fact,
16 and 49 isomerized at 130 °C, while the linear IMDA
substrates 14, 15, and 38 successfully afforded the corresponding
cycloadducts even at a higher reaction temperature (150 °C).
These phenomena are not in accord with the generally accepted
recognition that the TADA reaction using (E,Z)-dienes proceeds
more efficiently than the IMDA counterpart.40
Although the yields were disappointing, we were interested
in the stereochemical outcome of these TADA reactions. As in
the case of 38 (Figure 4), the diastereocontrol induced by the
C(8) stereogenic center in 16 and 49 may make the transition
states leading to 12 and 50 favorable. However, the TADA
substrates 16 and 49 preferably provided the cycloadducts 51a
and 50, respectively. These results could be explained by
considering the following two competing steric interactions. In
the case of the TADA reaction of 16, the diastereocontrol
induced by the bulky OTBS groups at C(14) and C(16) probably
exceeded that induced by the C(8) substituent, resulting in the
formation of the undesired cycloadduct 51a. On the other hand,
the smaller OMOM groups in 49 might have decreased the
unfavorable steric interaction, resulting in the formation of 50
under the diastereocontrol induced by the C(8) OMPM group.
Finally, we examined the IMDA reaction of substrate 17,
indicated as path D in Scheme 3 (Scheme 12). The substrate
17 was synthesized from 48a in a three-step sequence: (1)
deprotection of the TBS groups, (2) lactonization under basic
conditions,101 and (3) introduction of the C(2)-C(3) double
1
bond.102 The TADA substrate 17 showed a complicated H
NMR spectrum, making determination of the E/Z ratio extremely
difficult. We attribute this complication to the presence of
tautomers such as a hemiketal form and/or rotamers, in addition
to geometrical isomers about the C(2)-C(3) double bond. By
heating the macrocycle 17 to 130 °C, the desired tetracyclic
compound 1374 was obtained as a sole cycloadduct in an overall
yield of 47% from 48a. No diastereomer or geometrical isomer
was obtained. Contrary to the TADA reactions of the macro-
(101) Under acidic conditions, the desired δ-lactone was not obtained; however,
â-elimination of the C(16)-OH occurred to form a (Z)-R,â-unsaturated
ketone substructure.
(102) We also investigated the synthesis of 17 through a macroallylation strategy
applied to an allyl acetate or carbonate bearing the preexisting â-keto-δ-
lactone ring, but the yield of the macroallylation product was lower (ca.
30%) as compared to that obtained from the corresponding â-ketoester
derivative 47a (84%).
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11264 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004

Total Synthesis of Macquarimicins
A R T I C L E S
Figure 6. Plausible mechanisms for the stereoselectivity in the TADA of 17.
Scheme 13. Examination of the Intramolecular Knoevenagel
Reaction for 10 and 53
cycles 16 or 49, the TADA reaction of 17 proceeded successfully
to give 13 highly stereoselectively.
The stereochemical outcome observed in the TADA reaction
of 17 can be rationalized as follows (Figure 6). Considering
the (2Z)-isomer (Z)-17, two endo transition states, TS-C with
s-trans conformation through C(2)-C(5) and TS-D (with s-cis),
are possible. Comparing the two transition states, TS-C seems
to be considerably more favorable, considering that two severe
steric interactions are present in TS-D. One is a repulsion
generated between the OMPM group and H(12) as explained
for the stereoselectivity observed in the IMDA reactions of 14,
15, and 38 (Figure 4). The other is a repulsion between H(5)
and the lactone carbonyl oxygen. The cycloadducts derived from
the (2E)-isomer, (E)-17, were not observed. Each endo transition
state from (E)-17, TS-E or TS-F, suffers from one of the two
steric interactions present in TS-D. As both TADA transition
states seem to be disfavored, the (E)-17, if it existed, might
isomerize to its (Z)-isomer rather easily or decompose under
the reaction conditions.
The IMDA reactions of 14-17 proceeded at 130 °C or higher
temperatures. The low reactivity of these substrates contrasts
with the facts reported by the groups of Sorensen21 and Evans22
regarding their total synthesis of FR182877. In their cases, a
tandem transannular Diels-Alder sequence proceeded at 40 and
50 °C, respectively. On the basis of these observations, the two
groups indicated the possibility that FR182877 is biosynthesized
spontaneously from a monocyclic precursor through the cy-
cloaddition cascade. Assuming the involvement of an IMDA
reaction in the biosynthesis of macquarimicins and cochleamy-
cins, a spontaneous cycloaddition at ambient temperature seems
to be difficult considering the lower reactivity of (E,Z,E)- or
(E,E,Z)-1,6,8-nonatrienes observed in this study. Although we
still have no evidence, some kind of acceleration may participate
in the biosynthetic IMDA process for the macquarimicin and
cochleamycin cases.
prepared from 11 by removal of the MOM group with MgBr2‚
OEt2 and EtSH in Et2O,103 to a variety of conditions104 provided
none of the desired cyclized products. The â-keto-δ-lactone
moiety in 53 proved to be labile under the conditions employed,
resulting in the formation of an R,â-unsaturated methyl ke-
tone.105
Our attention was next focused on the construction of the
tetracyclic framework of 1 from the TADA cycloadduct 50. The
MPM group in 50 was first removed with DDQ, and the
(103) The deprotection, proceeding in 64% yield, accompanied the formation
of a dithioacetal.
(104) We examined a variety of reagents such as amino acids (â-alanine,
L-proline), amines (piperidine, pyrrolidine), ammonium salts (ethylene-
diamine diacetate, piperidinium acetate), and combinations of a Lewis
acid and an amine (TiCl4/pyridine, MgBr2‚OEt2/lutidine).
(105) The R,â-unsaturated ketone might be produced by sequential â-elimination
and decarboxylation as shown below.
Completion of the Total Synthesis. To achieve the total
synthesis of macquarimicins, transformations of the aforemen-
tioned cycloadducts were investigated. As summarized in
Scheme 3, we first explored the intramolecular Knoevenagel
reaction for 10 and 11 to construct the 10-membered carbocycle
(C-ring) of 1 (Scheme 13). The exposure of 10 or 53, the latter
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J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004 11265

A R T I C L E S
Munakata et al.
Scheme 14. Attempt To Convert the Cycloadduct 50 to
Macquarimicin A (1)
Figure 7. NOE experiments of 1.
Scheme 15. Total Synthesis of Macquarimicins
resultant C(8)-OH was oxidized with Dess-Martin periodinane
to give ketone 54 (Scheme 14). Deprotection of two MOM
groups in 54 would provide diol 55, which would be followed
by lactonization to afford, eventually, macquarimicin A (1).
Unfortunately, treatment of 54 with Brønsted or Lewis acid
(HCl, CF3CO2H, B-bromocatecholborane, TMSBr, or BBr3)
provided neither diol 55 nor 1. We did not conduct further
exploration using 50 due to its low yield observed in the TADA
reaction of 49.
Finally, the total synthesis of 1 from 13, the TADA
cycloadduct equipped with the ABCD ring, was investigated.
Protection of the C(14)-OH in 13 as a TES ether, followed by
removal of the MPM group, gave 56 (Scheme 15). Dess-Martin
oxidation of 56 and subsequent PPTS-catalyzed cleavage of the
TES ether afforded (+)-macquarimicin A (1) uneventfully. The
spectral properties (1H and 13C NMR and IR) of synthetic (+)-1
were completely identical to those of a natural sample, and
optical rotation of synthetic (+)-1 ([R]23 ) +270; c 0.20,
D
MeOH) established the absolute configuration of natural (+)-1
([R]25D ) +285.6; c 0.2, MeOH).3 Furthermore, extensive NOE
experiments on synthetic (+)-1 revealed that the C(2)-C(3)
geometry must be Z but not E as was originally reported1b,106
(Figure 7).
To complete the total synthesis of other members of mac-
quarimicins, the conversion of macquarimicin A (1) into
macquarimicin B (2) and then C (3) was attempted. On treatment
of 1 with 2-methoxypropene in THF-H2O, the expected
intermolecular hetero Diels-Alder reaction took place smoothly,
and then spontaneous hydrolysis of the transient cycloadduct
occurred to provide 2 in a good yield of 83%. To convert 2 to
3, a dehydrative transannular alkylation is required. Assuming
that C(14) of 3 has the same stereochemistry as cochleamycin
B (6), the configuration of C(14) in 2 must be inverted through
the cyclization. In fact, the desired transformation was effected
by treatment of 2 with CSA in dichloromethane to produce 3
quantitatively. The stereoselectivity of the two reactions from
1 to 3 is well explained as depicted in Figure 8. In the hetero
Diels-Alder reaction of 1 with 2-methoxypropene,107 the
dienophile approaches from the outer side of the C ring in 1,
and this means the stereochemistry at C(3) in 2 is the same as
the natural product. As an AM1 calculation31 suggests the
efficient overlap of π(C2-C18) and σ*(C14-OH2+) orbitals in
(107) For examples of hetero Diels-Alder reactions using 2-methoxypropene
as a dienophile, see: (a) Sato, M.; Kano, K.; Kitazawa, N.; Hisamichi,
H.; Kaneko, C. Heterocycles 1990, 31, 1229-1232. (b) Cravotto, G.;
Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetrahedron: Asymmetry
2001, 12, 707-709. (c) Nair, V.; Tressa, P. M. Tetrahedron Lett. 2001,
42, 4549-4551.
(106) As shown in Figure 7, irradiations at H(3) and H(14) led to the
enhancement of the signals of H(14) and H(17a), respectively. These
results indicate that the three hydrogen atoms are located on the same
side of the 10-membered ring. Therefore, the C(2)-C(3) geometry was
determined to be Z.
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11266 J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004

Total Synthesis of Macquarimicins
A R T I C L E S
Figure 9. NOE experiments on 3 and 58.
from cochleamycin A (4) and A2 (5), respectively, by employing
the conditions developed for the transformation of 57 into 58.
Figure 8. Plausible mechanism of the stereoselectivity observed in the
transformation of 1 to 3.
Conclusion
The first total syntheses of the macquarimicins A-C (1-3)
and unnatural 9-epi-cochleamycins A (57) and B (58) have been
accomplished. The key step in their total syntheses is the
construction of the unique polycyclic molecular framework by
a biosynthesis-based intramolecular Diels-Alder reaction. To
synthesize the IMDA substrates (14-17) with the (Z,E)-diene
moiety, a convergent union of a variety of intermediates by a
modified Stille coupling strategy was successfully applied. The
IMDA reactions including TADA reactions conducted using
(E,Z,E)-1,6,8-nonatrienes are quite beneficial in the field of
complex natural product synthesis. A model study comparing
the reactivity of (E,Z,E)- and (E,E,Z)-1,6,8-nonatrienes was
performed. It implied the potential advantage of the (E,Z,E)-
trienes for the construction of cis-anti-cis tetrahydroindanes. In
the present synthesis, (+)-macquarimicin A (1) was synthesized
with 40 total steps and 27 linear steps from either 22 or 30 in
4.3% or 9.9% overall yields, respectively (92% or 89% average
yield per step, respectively). Macquarimicins B (2) and C (3)
were also synthesized from 1 in one or two more steps,
respectively, guided by a hypothetical biosynthetic pathway. The
present total synthesis reveals the intrinsic reactivity of these
natural products. The seven to nine stereogenic centers in the
macquarimicins and 9-epi-cochleamycins were constructed by
five diastereoselective transformations in a completely stereo-
selective manner, utilizing the two stereogenic centers in the
starting materials 22 and 30. In addition, the present work
established the absolute configuration of (+)-1 and the relative
configuration of 3 and revised the C(2)-C(3) geometry of 1.
Scheme 16. Synthesis of 9-epi-Cochleamycins
protonated 2, the transannular alkylation proceeds in an SN2
manner to produce 3 with complete inversion of the configu-
ration as shown in the second brackets.
To test the applicability of the transformation of 1 to 3
developed above, we explored the synthesis of the 9-epi series
of cochleamycin (Scheme 16). The hydroxyl group in 56 was
acetylated using Ac2O and DMAP in CH2Cl2.108 The TES group
of the resultant acetate was removed with PPTS in MeOH to
produce 9-epi-cochleamycin A (57). The 1H NMR spectrum of
57 showed a pattern similar to that of cochleamycin A (4) except
signals for the A-ring. The 1,4-hydride addition to 57 with
NaBH4 produced a transient â-keto-δ-lactone derivative, which
was immediately converted into 9-epi-cochleamycin B (58) with
CSA in 71% yield from 57.
The stereochemistries of C(14) of 3 and C(16) of 58 were
both determined to be S based on NOE difference experiments
as shown in Figure 9. Thus, it was established that 3 has the
same stereochemistry as cochleamycin B (6) and B2 (7). From
these results, 6 and 7 might be synthesized stereoselectively
Acknowledgment. This research was supported by Grants-
in-Aid for Scientific Research on Priority Areas (A) “Targeted
Pursuit of Challenging Bioactive Molecules” and for the 21st
Century COE program “KEIO LCC” from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan.
We thank Dr. Takeshi Ogita (Sankyo Co., Ltd.) for providing
us with a sample and spectroscopic data of natural macquar-
imicin A, and Daiso Co., Ltd., for providing (R)-epichlorohydrin.
Supporting Information Available: Experimental procedures,
characterization data, and 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(108) The use of usual conditions such as Ac2O/pyridine or AcCl/Et3N/CH2Cl2
led to complex mixtures.
JA048320W
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J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004 11267