Total synthesis of mycalamide a and 7-epi-mycalamide A

Article abstract of DOI:10.1021/ol005629l

formula presented The final stages of a total synthesis of mycalamide A are described. A key step is the aldol reaction (mismatched) of imide 4 and aldehyde 5 which provided a ca. 5:4 mixture of aldols 10a and 10b, with incorrect C(7) stereochemistry. Ela

Full text of DOI:10.1021/ol005629l

ORGANIC
LETTERS
2000
Vol. 2, No. 6
859-862
Total Synthesis of Mycalamide A and
7-epi-Mycalamide A
William R. Roush* and Lance A. Pfeifer
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received February 5, 2000
ABSTRACT
The final stages of a total synthesis of mycalamide A are described. A key step is the aldol reaction (mismatched) of imide 4 and aldehyde
5 which provided a ca. 5:4 mixture of aldols 10a and 10b, with incorrect C(7) stereochemistry. Elaboration of the 10a−10b mixture to mycalamide
A required epimerization of C(7) at the stage of â-keto imide 11. Alternatively, Swern oxidation of the 10a−10b mixture under conditions that
minimize C(7) epimerization led to 7-epi-mycalamide A selectively.
Mycalamide A is a member of a group of marine natural
products which display potent antiviral and antitumor
activity.1-4 Mycalamide A has been shown to transform ras-
mutated NRK cells to normal morphology at e10 ng/mL
concentration through inhibition of P21.4 The mycalamides
also display immunosuppressive activity via inhibition of
CD4+ T-cell activation and are significantly more potent than
either FK-506 or cyclosporin A in this assay.5 The mycala-
mides are structurally related to the onnamides and theope-
derins, which differ from the mycalamides principally in the
C(15) side chain,6-8 as well as pederin, an insect toxin.9 As
a result of their potent biological properties, this family of
natural products has attracted considerable attention as targets
for total synthesis. Kishi reported pioneering total syntheses
of mycalamides A and B, as well as of onnamide A,10,11 while
Nakata has completed a total synthesis of mycalamide A.12-14
Kocienski has reported total syntheses of 18-O-methyl-
mycalamide B, mycalamide B, and theopederin D.15-17 In
addition, studies on the synthesis of the mycalamides have
been reported by Hoffmann18-20 and ourselves.21-24 We
(10) Hong, C. Y.; Kishi, Y. J. Org. Chem. 1990, 55, 4242.
(11) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.
(12) Nakata, T.; Matsukura, H.; Jian, D.; Nagashima, H. Tetrahedron
Lett. 1994, 35, 8229.
(13) Nakata, T.; Fukui, H.; Nakagawa, T.; Matsukura, H. Heterocycles
1996, 42, 159.
(14) We refer to the right-hand, amine component of the mycalamides
as “mycalamine”.
(15) Kocienski, P.; Raubo, P.; Davis, J. K.; Boyle, F. T.; Davies, D. E.;
Richter, A. J. Chem. Soc., Perkin Trans. 1 1996, 1797.
(16) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. T.
Synlett 1998, 869.
(1) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K. J. Am.
Chem. Soc. 1988, 110, 4850.
(2) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson, A. M. J.
Org. Chem. 1990, 55, 223.
(3) Burres, N. S.; Clement, J. J. Cancer Res. 1989, 49, 2935.
(4) Ogawara, H.; Higashi, K.; Uchino, K.; Perry, N. B. Chem. Pharm.
Bull. 1991, 39, 2152.
(5) Galvin, F.; Freeman, G. J.; Razi-Wolf, Z.; Benacerraf, B.; Nadler,
L.; Reiser, H. Eur. J. Immunol. 1993, 23, 283.
(6) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T. J. Am. Chem.
Soc. 1988, 110, 4851.
(7) Matsunaga, S.; Fusetani, N.; Nakao, Y. Tetrahedron 1992, 48, 8369.
(8) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992, 57,
3828.
(17) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. T.
Synlett 1998, 1432.
(18) Hoffmann, R. W.; Schlapbach, A. Tetrahedron Lett. 1993, 34, 7903.
(19) Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. HelV. Chim. Acta
1996, 79, 346.
(20) Breitfelder, S.; Schlapbach, A.; Hoffmann, R. W. Synthesis 1998,
468.
(9) Frank, J. H.; Kanamitsu, K. J. Med. Entomol. 1987, 24, 67, and
references therein.
(21) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34, 5421.
(22) Marron, T. G.; Roush, W. R. Tetrahedron Lett. 1995, 36, 1581.
10.1021/ol005629l CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/03/2000

report herein the completion of our total synthesis of
mycalamide A (Scheme 1).
presumably due to destabilizing steric congestion of the
transition state.
These difficulties prompted us to explore a strategy for
completing the mycalamide synthesis through the aldol
reaction of 4 and 5, which we successfully modeled by using
the readily available N-D-glycosyl imide 6 as a surrogate for
4. We established that the aldol reaction of 5 and 6 provided
the syn aldol 7 with g 20:1 selectivity and elaborated this
intermediate into the N-glycosyl pederamide derivative 8 via
an efficient, six-step sequence (Scheme 3).24 In the course
Scheme 1
Scheme 3
One of the significant challenges associated with the
synthesis of this family of natural products concerns control
of the stereochemistry at the C(7) and C(10) stereocenters.
Despite the considerable effort devoted to the synthesis of
these molecules, no completely stereoselective route to any
member of the family has yet appeared. All syntheses to date,
including the synthesis reported herein, have involved
generation of mixtures at one or both of these key centers.
We correctly predicted and demonstrated as early as 1993
that the C(10) stereocenter could be controlled via the Curtius
reaction of a C(10) carboxylic acid precursor.21 Moreover,
we subsequently demonstrated that N-acylation reactions of
R-alkoxycarbamates, including 2, could be accomplished
under basic conditions without epimerization of the labile10
C(10) stereocenter.25,26 However, our initial efforts to com-
plete a total synthesis were compromised by the steric
congestion surrounding the C(6) ketal and C(10)-N units,
which prevented the union of 123 and 222 from being
successfully accomplished (Scheme 2).24,25 Moreover, we
Scheme 2
of these studies, we determined that the chlorotitanium
enolate of 6 was only moderately diastereoselective (ca. 2:1)
in reactions with benzaldehyde and concluded that the
excellent stereochemical control in the aldol reaction of 5
and 6 was governed by the intrinsic diastereofacial preference
of the â-alkoxy aldehyde to favor production of 1,3-anti
product.27 However, since 4 and 6 are in opposite enantio-
meric series, we recognized that the 4 + 5 coupling might
be a mismatched fragment assembly aldol reaction.28
Nevertheless, we were optimistic that good results would
be achieved since it was not obvious at the outset that the
intrinsic diastereofacial selectivity of 4 should be any greater
than that of 6. That is, we anticipated that 5 would be the
dominant stereochemical contributor in the targeted aldol
reaction with 4.
subsequently discovered that attempted coupling of 2 and
the acyclic acid chloride 3 was also unsuccessful, again
(25) Marron, T. G. Ph.D. Thesis, Indiana University, 1995.
(26) Roush, W. R.; Pfeifer, L. A. J. Org. Chem. 1998, 63, 2062.
(27) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322.
(23) Roush, W. R.; Marron, T. G.; Pfeifer, L. A. J. Org. Chem. 1997,
62, 474.
(24) Roush, W. R.; Pfeifer, L. A.; Marron, T. G. J. Org. Chem. 1998,
63, 2064.
(28) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1.
860
Org. Lett., Vol. 2, No. 6, 2000

The synthesis commenced with the Curtius reaction of
carboxylic acid 9,22 which provided the 2-trimethylsilylethyl
carbamate (Teoc) protected amine 2 in 83% yield under
optimized conditions (Scheme 4).29 Treatment of a mixture
mixture of aldols was increased to 84%. The sensitivity of
the aldol products to N f O transfer of the Teoc group under
even weakly basic conditions (e.g., upon exposure to Et3N
at -78 °C) precluded use of lithium enolate aldol technology.
Attempts to perform the aldol reaction using enolborane
derivatives generated from 4 were unsuccessful.
The two major isomers 10a and 10b could be separated
only with considerable loss of material during chromatog-
raphy, owing to their sensitivity to N f O Teoc group
migration.32 Consequently, the aldol mixture typically was
used directly in the following sequence. Oxidation of the
mixture with the TFAA-DMSO Swern reagent33 under
non-epimerizing conditions (vide infra) provided the â-keto
imide 11 in good yield, with the caveat that it was necessary
to add the aldols to the Swern reagent before addition of
Et3N; otherwise, N f O Teoc transfer proved highly
competitive with the oxidation reaction. Treatment of crude
â-keto imide 11 with camphorsulfonic acid (CSA) in MeOH
then provided the epimeric methyl ketals 12 and 13 in 53%
and 11% yields, respectively. Ketal 12 was also obtained
when partially purified (but separated)32 samples of either
10a or 10b were subjected to the oxidation-ketalization
sequence, thus establishing that the two major aldols have
the same stereochemistry at C(7). That this center corre-
sponds to the unnatural C(7)-R stereochemistry was estab-
lished by elaboration of 12 to C(7)-epi-mycalamide A by
the following four-step sequence. Oxidation of C(4)-OH by
using the standard DMSO-(COCl)2 Swern protocol,33 fol-
lowed by Takai-Nozaki methylenation,34 removal of the
Teoc unit by treatment with TBAF in DMF at 0 °C, and
then reductive cleavage of the C(7)-O-benzyl group and
the C(17,18)-carbonate unit provided 7-epi-mycalamide A
in 49% overall yield. The identity of synthetic 7-epi-
mycalamide A was confirmed by comparison with 1H NMR
data kindly provided by Dr. T. Nakata.35
Scheme 4
It is clear from these results that the aldol reaction of 4
and 5 followed a totally different stereochemical course than
that anticipated on the basis of our earlier studies of the aldol
reaction of 6 and 5.24 That the two major aldols 10a and
10b possess unnatural C(7)-R stereochemistry indicates that
the chlorotitanium enolate of 4 exerts a significant diaste-
reofacial influence, such that the aldol reaction with 5 is
significantly mismatched.28 This effect was also observed
in aldol reactions of 4 and Me2CHCHO (TiCl4, i-Pr2NEt,
CH2Cl2, -78 °C), which provided a ca. 10:5:1 mixture of
three aldols, the two major isomers of which were assigned
C(7)-R stereochemistry by spectroscopic correlation with
10a,b. At present we attribute the diastereofacial selectivity
of 2 and DMAP with LiN(TMS)2 in THF at -78 °C followed
by addition of BnOCH2COCl provided imide 4 in 92% yield
with complete preservation of the C(10) stereocenter,26
thereby setting the stage for the key aldol reaction. In the
event, the chlorotitanium enolate was generated by treatment
of 4 with TiCl4 and i-PrNEt2 in CH2Cl2 at -78 °C,30,31 and
then a CH2Cl2 solution of â-alkoxy aldehyde 5 (1.2-1.5
equiv) was added. This reaction afforded a ca. 5:4:1:1
mixture of four aldols in up to 69% yield, along with 29%
of recovered imide 4. After recycle of 4, the yield of the
(32) Aldol 10b was obtained pure by chromatography, but 10a was
otained as a ca. 5:1:1 mixture with the two minor diastereomers.
(33) Tidwell, T. T. Org. React. 1990, 39, 297.
(34) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1985,
26, 5579.
(35) Fukui, H.; Tsuchiya, Y.; Fujita, K.; Nakagawa, T.; Koshino, H.;
Nakata, T. Biorg. Med. Chem. Lett. 1997, 7, 2081.
(29) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203.
(30) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215.
(31) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(36) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1992, 31, 1124.
(37) Molecular mechanics calculations reveal that the C(10)-H eclipses
one of the imide carbonyl groups in 4, although the energy difference
between the two C(10)-N rotamers is very small. We assume that this
eclipsed conformation is maintained in the chlorotitanium enolate, as
indicated in 14.
Org. Lett., Vol. 2, No. 6, 2000
861

of the chlorotitanium enolate 14 to the C(15) side chain (not
present in 6) which effectively blocks the backside of the
enolate from approach of the aldehyde (Scheme 5). The
Scheme 6
Scheme 5
C(15) side chain is forced to adopt the conformation indicated
so as to minimize syn-pentane interactions with the C(14)
substituents.36 Although models indicate that the C(10)-imide
functionality can readily adopt a second low-energy confor-
mation by 180° rotation about the C(10)-N bond in 14,37
our model analysis indicates that C(17)-O is close enough
to interact with the chlorotitanium enolate, perhaps as a
ligand on titanium, such that the rotamer depicted in Scheme
5 corresponds to the kinetically dominant one. Aldol reac-
tions of enolate 14 by necessity should occur preferentially
from the front face, leading to the 7(R)-aldol stereochemistry
present in both 10a and 10b. However, the factors that
contribute to the poor selectivity for chairlike vs boatlike
transition states in aldol reactions of 14 (which accounts for
the low level of control over the C(6) stereochemistry in the
aldol mixture) are unclear at present.
To complete the mycalamide synthesis, we returned to the
Swern oxidation of the 10a,b mixture. Merely switching
bases from i-Pr2NEt to Et3N, and allowing the reaction
mixture to warm from -78 to 0 °C after addition of Et3N,
provided a ca. 1:1 mixture of 11 and its C(7)-epimer 15
(Scheme 6). Treatment of this mixture with CSA in MeOH
then provided an easily separable mixture of 13 (31% for
the two-step sequence from 10a,b) and 12 (27% yield).
Oxidation of the free C(4)-hydroxyl group of 13 followed
by Takai-Nozaki olefination provided 16 in 58% yield.
Finally, removal of the 2-(trimethylsilyl)ethyl carbamate
(Teoc) by treatment of 16 with TBAF in DMF at 0 °C
followed by reductive cleavage of the C(7)-O-benzyl ether
and the C(17,18) carbonate provided synthetic mycalamide
A in 84% yield. The identity of this material was confirmed
by comparison with an authentic sample of synthetic my-
calamide A generously provided by Prof. Kishi.10 The
spectroscopic properties of our synthetic material were also
in excellent agreement with data kindly supplied by Prof.
Munro.1,2
In summary, total syntheses of mycalamide A and 7-epi-
mycalamide A have been completed. This work nicely
illustrates the utility of our carbamate acylation protocol22,26
for controlling the C(10)-R-alkoxy amide stereocenter of the
natural product. Moreover, our synthesis of 7-epi-mycalamide
A35 constitutes the first stereoselective synthesis of any
member of this family. However, additional efforts will be
required for definition of a strategy for control of both the
C(10) and C(7) stereocenters of the mycalamides and related
natural productssa problem that has not been solved in any
of the syntheses reported to date.10-13,15-17,38-40
Acknowledgment. Support provided by the National
Institutes of Health (GM 38907) is gratefully acknowledged.
We also thank Drs. Nakata and Munro for providing
spectroscopic data and Prof. Kishi for providing an authentic
sample of mycalamide A for comparison.
Supporting Information Available: Experimental pro-
cedures for the synthesis of 4-19, epi-mycalamide A, and
mycalamide A, plus tabulated spectroscopic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(38) Willson, T. M.; Kocienski, P.; Jarowicki, K.; Isaac, K.; Faller, A.;
Campbell, S. F.; Bordner, J. Tetrahedron 1990, 46, 1757.
(39) Kocienski, P.; Jarowicki, K.; Marczak, S. Synthesis 1991, 1191, and
references therein.
(40) Nakata, T.; Nagao, S.; Oishi, T. Tetrahedron Lett. 1985, 26, 6465.
References to earlier syntheses of pederin are cited in this paper.
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