Stereocontrolled synthesis of (-)-macrolactin A

Article abstract of DOI:10.1021/ja017177t

The total synthesis of (-)-macrolactin A, a 24-membered macrolide, has been achieved using a newly developed 1,3-diol synthon for the introduction of two key stereogenic centers. The synthon was derived from sequential use of the Noyori asymmetric reduction followed by chiral sulfoxide methodology. Tellurium-derived cuprate organometallics offered an efficient and highly stereoselective means for installation of the C8 Z/E-diene, while the C15 E/E-segment was derived from a Julia-Lythgoe olefination. Yamaguchi lactonization was used to secure the macrocycle in a convergent approach with the longest linear sequence of 19 steps from Noyori alcohol 6.

Full text of DOI:10.1021/ja017177t

Published on Web 01/31/2002
Stereocontrolled Synthesis of (-)-Macrolactin A
Joseph P. Marino,*,† Michael S. McClure,*,† David P. Holub,†
Joa˜o V. Comasseto,‡ and Fab´ıo C. Tucci‡
Contribution from the Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan
48109, and Instituto de Qu´ımica, UniVersidade de Sa˜o Paulo, Sa˜o Paulo 26077, Brazil
Received September 27, 2001. Revised Manuscript Received November 30, 2001
Abstract: The total synthesis of (-)-macrolactin A, a 24-membered macrolide, has been achieved using
a newly developed 1,3-diol synthon for the introduction of two key stereogenic centers. The synthon was
derived from sequential use of the Noyori asymmetric reduction followed by chiral sulfoxide methodology.
Tellurium-derived cuprate organometallics offered an efficient and highly stereoselective means for
installation of the C8 Z/E-diene, while the C15 E/E-segment was derived from a Julia-Lythgoe olefination.
Yamaguchi lactonization was used to secure the macrocycle in a convergent approach with the longest
linear sequence of 19 steps from Noyori alcohol 6.
Introduction
The macrolactins are a structurally diverse class of secondary
metabolites isolated from a deep-sea bacterium.1 The parent
aglycone, macrolactin A (Figure 1), is representative. Some
members of this class possess pendant glucose-â-pyrannosides,
while others differ in the oxidation state and degree of
unsaturation. Macrolactin A exhibits a broad spectrum of activity
with significant antiviral and cancer cell cytotoxic properties
including inhibition of B16-F10 murine melanoma cell replica-
tion with in vitro IC50 values of 3.5 µg/mL. Macrolactin A also
has implications for controlling human HIV replication and is
a potent inhibitor of Herpes simplex types I and II. Because of
its unique structural architecture and the potential for broad
therapeutic applications, macrolactin A has been an attractive
target for synthesis and has further led to the development of
novel synthetic methodology.2 Fenical and co-workers discov-
ered the macrolactins1 and reported with their initial findings
general structural assignments for macrolactins A-F. The
absolute stereochemistry was later established for macrolactins
B and F through degradation, chemical correlation, and 13C-
acetonide analysis.3 The stereochemical assignments for mac-
rolactin A were made initially through comparative spectral data,
but later were confirmed by Smith and Ott in the first total
Figure 1. (-)-Macrolactin A.
synthesis4 and later by Carreira and co-workers.5 Synthetic
efforts are essential for additional pharmacological investigations
and understanding the mode of action of these molecules.
Typical recoveries from 16 L of cell culture give 6-9 mg of
macrolactin A and less of the other macrolactins. Notably, the
bacterial source of the macrolactins apparently no longer
produces macrolactins A-E, only F.2a
Results and Discussion
We report herein the stereocontrolled synthesis of (-)-
macrolactin A based upon four principal components 2-5
(Scheme 1). This synthesis features the transmetalation of a
stereodefined Z-vinylic telluride, the novel application of chiral
sulfoxides, and the critical use of a recently developed, versatile
1,3-diol synthon. Our key disconnection involved assembly of
advanced intermediates 2 and 3 via a Julia-Lythgoe6 coupling.
The northern portion of the molecule containing the C7
stereocenter we envisioned would involve the asymmetric
addition of an organometallic, formally represented as subunit
5. Macrocyclic ring closure would consummate the synthesis
* To whom correspondence should be addressed. M.S.M., current
address: GlaxoSmithKline, Chemical Development, Research Triangle Park,
NC 27709.
† University of Michigan.
‡ Universidade de Sa˜o Paulo.
(1) Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc. 1989, 111, 7519.
(2) (a) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095. (b)
Boyce, R. J.; Pattenden, G. Tetrahedron Lett. 1996, 37, 3501. (c) Donaldson,
W. A.; Bell, P. T.; Wang, Z.; Bennett, D. W. Tetrahedron Lett. 1994, 35,
5829. (d) Prahlad, V.; Donaldson, W. A. Tetrahedron Lett. 1996, 37, 9169.
(e) Tanimori, S.; Morita, Y.; Tsubota, M.; Nakayama, M. Synth. Commun.
1996, 26, 559. (f) Benvegnu, T.; Schio, L.; Le Floc’h, Y.; Gre´e, R. Synlett
1994, 505. (g) Benvegnu, T. J.; Gre´e, R. L. Tetrahedron 1996, 52, 11821.
(3) Rychnovsky, S. D.; Skalitzky, D. J.; Pathirana, C.; Jensen, P. R.; Fenical,
W. J. Am. Chem. Soc. 1992, 114, 671.
(4) Reference 2a and Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1998,
120, 3935.
(5) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew. Chem., Int. Ed. 1998, 37,
1261.
(6) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833.
9
1664 VOL. 124, NO. 8, 2002 J. AM. CHEM. SOC.
10.1021/ja017177t CCC: $22.00 © 2002 American Chemical Society

Stereocontrolled Synthesis of (−)-Macrolactin A
A R T I C L E S
Scheme 1
Figure 2. 1,3-Diol synthon.
Scheme 2
through intramolecular Pd-catalyzed Stille cross-coupling7 or
by traditional macrolactonization.8
Enal 2 contains a 1,3-diol motif which is common to four of
the macrolactins. We have designed a bifunctional 1,3-diol
synthon (Figure 2)9 with this subunit in mind. Because this motif
is ubiquitous among polyol and polyfunctional natural prod-
ucts,10 this synthon could enjoy general use in natural product
synthesis. Nucleophilic ring opening of the epoxy terminus
allows extension in one direction, while manipulation of the
R-carbon occurs through use of Pummerer-type11 conditions.
The requisite diastereomer for macrolactin A was prepared
according to Scheme 2. Noyori reduction12 of ethyl 4-chloro-
acetoacetate furnished â-hydroxy ester 6 which was subse-
quently protected as its tert-butyldimethylsilyl (TBS) ether.
Addition of the anion of (RS)-(+)-methyl p-tolyl sulfoxide13 to
the ester terminus afforded â-ketosulfoxide 8. Stereoselective
reduction14 with DIBAL (d.s. g 97:3) gave hydroxy sulfoxide
9 as a single diastereomer after crystallization. Epoxide 10
formed smoothly upon treatment with cesium(I) fluoride in THF/
CH3CN. All four diastereomers of the diol motif have been
prepared using this methodology.9 Naturally the enantiomer of
the Noyori catalyst can be used to produce the diastereomer at
the δ position. Additionally, chelation-controlled reduction of
the â-ketosulfoxide 8 can be used to generate diastereomers at
the â position. The requirement for CsF in the epoxide formation
step is also worth noting. While CsF did cleanly deliver the
epoxide, we also explored other reagents such as NaOH.
Interestingly, almost exclusive furan formation resulted from
5-endo cyclization of the hydroxy â to the sulfoxide. The cesium
ion arguably plays a role in coordination to the adjacent chlorine,
allowing for facile epoxide formation.9
Scheme 3
12. While the stereoselectivity of this reaction has been well
established,15 to our knowledge this is the first reported use of
vinyl tellurides in the synthesis of a natural product. Trans-
metalation15 with a mixed higher-order cyanocuprate occurs at
room temperature. Subsequent addition of epoxide 10 gave the
anti 1,3-diol 13. Two equivalents of the curprate and use of
unprotected alcohol 10 were required. When the alcohol is
protected as its methyl or silyl ether, â-elimination results, thus
lowering significantly the yield of the desired adduct. Ring
opening of the epoxy terminus occurs readily at room temper-
ature under very mild conditions. After protection of diol 13 as
its acetonide derivative, the aldehyde was unveiled through a
Pummerer reaction on the sulfoxide terminus of 14. This
aldehyde was surprisingly stable when buffered mercury(II)
chloride (pH 6.7) was employed in the hydrolysis of the
Pummerer intermediate. Epimerization of the R stereocenter was
not observed. Wittig homologation of aldehyde 15 gave subunit
2 as a single stereoisomer which set the stage for coupling to
3.
Completion of subunit 2 was achieved by opening the epoxy
terminus of 10 with a tellurium-derived cuprate (Scheme 3).
(E)-Pent-2-ene-4-yne-1-ol was protected as its TBS ether 11
and stereoselectively hydrometalated to give vinylic telluride
(7) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions; Paquette,
L. A., Ed.; John Wiley and Sons: New York, 1997; Vol. 50, pp 1-652.
(8) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
Installation of the C23 stereocenter in subunit 3 occurred
through diastereoselective reduction of â-ketosulfoxide 16
(Scheme 4).14 The anion of (RS)-(+)-methyl p-tolyl sulfoxide
was added to methyl 5-benzyloxypentanoate16 to give â-keto-
(9) Holub, D. P. Ph.D. Dissertation, University of Michigan, 1995.
(10) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021.
(11) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
(12) Kitamura, M.; Ohkuma, T.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1988,
29, 1555.
(13) Anderson, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins,
R. I. J. Am. Chem. Soc. 1964, 86, 5637.
(14) (a) Solladie´, G.; Maestro, M. C.; Rubio, A.; Pedregal, C.; Carren˜o, M. C.;
Ruano, J. L. G. J. Org. Chem. 1991, 56, 2317. (b) Solladie´, G.; Greck, C.;
Demailly, G.; Solladie´-Cavallo, A. Tetrahedron Lett. 1982, 23, 5047.
(15) Tucci, F. C.; Chieffi, A.; Comasseto, J. V.; Marino, J. P. J. Org. Chem.
1996, 61, 4975.
(16) Nakao, R.; Oka, K.; Fukumoto, T. Bull. Chem. Soc. Jpn. 1981, 54, 1267.
9
J. AM. CHEM. SOC. VOL. 124, NO. 8, 2002 1665

A R T I C L E S
Marino et al.
Scheme 4
Scheme 6
Scheme 5
1
confirmed by H NMR using nOe enhancements. The most
telling effect was observed upon irradiation of the allylic
methylene. Treatment of sulfone 22 with samarium diiodide20
delivered diene 21 as a mixture of diastereomers (8:2, E/Z).
The intermediacy of a vinyl radical in this process has been
proposed,20 and thus the formation of E/E isomers depends on
a facile equilibration of the vinyl radical prior to H-abstraction.
While this approach afforded a modest improvement over the
standard Julia approach, we felt that further exploration was
warranted. Interestingly, the olefinic selectivity problem was
resolved by returning to the original Julia method. Use of
benzoate rather than acetate (Scheme 5) resulted in a diaster-
eomeric ratio of 92:8 (E/Z). The undesired isomer could be
easily removed by chromatography. This result was indeed
fortuitous. We postulated that the improvement in stereoselec-
tivity may be attributed to the greater propensity of the
benzoyloxy group toward elimination (Ka ) 6.46 × 10-5 vs
acetic acid Ka ) 1.76 × 10-5). Keck and co-workers have nicely
demonstrated using deuterium labeling studies that two mech-
anisms are likely to be operative in the Julia-Lythgoe reaction
and that the pathway depends heavily on the reducing agent.20
Interestingly, they suggest that elimination to the vinyl sulfone
is the first step when Na(Hg) is employed. Subsequent reduction
steps then lead to the olefin.
With 21 in hand, the stage was set for installation of the final
stereogenic center. Selective deprotection of the TBS group was
desirable; however, when TBAF was employed at room
temperature, competitive cleavage of the triisopropylsilyl group
occurred and thus necessitated the use of lower temperature.
The use of TBAF in THF at -5 °C led cleanly to alcohol 23
(Scheme 7). Initial attempts to oxidize the alcohol to aldehyde
24 using Dess-Martin conditions24 resulted in stereoscrambling
of the conjugated dienal, giving an inseparable mixture of E/E,Z/
E-aldehyde and E/E,E/E-aldehyde in a 4:1 ratio. A control
experiment with isolated aldehyde suggested that the isomer-
ization was not caused by the Dess-Martin reagent itself, but
may be promoted by acetic acid. Oxidation with tetrapropy-
lammonium peruthenate (TPAP)25 with 4-methylmorpholine
N-oxide was found be be superior in this case, providing the
desired aldehyde 24 in 77% yield free of contamination from
the undesired diastereomer.
sulfoxide 16. Reduction with DIBAL (d.s. g 97:3) and
protection of the alcohol as its triisopropylsilyl ether gave
sulfoxide 17. Concomitant removal of the benzyl protecting
group and the sulfoxide terminus was accomplished with freshly
prepared W-4 Raney nickel17 and sonication.9 Treatment of
alcohol 19 with bromine and triphenylphosphine18 gave bromide
20 which was substituted with sodium benzene sulfinate19 to
afford the desired sulfone 3.
Convergent coupling of subunits 2 and 3 was accomplished
using a Julia-Lythgoe protocol. Sulfone 3 was treated with
n-butyllithium and coupled to enal 2 (Scheme 5). The alkoxy
anion was trapped in situ with acetyl chloride prior to treatment
with 6% sodium amalgam. Unfortunately, the stereoselectivity
of the elimination in this case was only 2:1, E/Z. We
subsequently evaluated the Keck variant20 of the Julia reaction
which involves the isolation of dienyl sulfone 22 (Scheme 6).
A mixture of acetoxy sulfones was initially treated with
diazobicyclo[5.4.0]undec-7-ene (DBU) at room temperature.
Unfortunately, this led to a mixture of alkenyl sulfone and
isomerized allyl sulfone.21 However, potassium tert-butoxide
in tert-butyl alcohol22 at room temperature afforded dienyl
sufone 22 as a single diastereomer. The stereochemistry23 was
(17) Pavlic, A. A.; Adkins, H. J. Am. Chem. Soc. 1946, 68, 1471.
(18) Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. J. Am. Chem.
Soc. 1964, 86, 964.
(19) Solladie´, G.; Lohse, O. J. Org. Chem. 1993, 58, 4555.
(20) Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194.
(21) O’Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840.
(22) Otera, J.; Misawa, H.; Sugimoto, K. J. Org. Chem. 1986, 51, 3830.
(23) While it is not immediately obvious why a single diastereomer is produced,
this result is consistent with previous examples, see ref 20. An E1cb
mechanism may be operative.
(24) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(25) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
9
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Stereocontrolled Synthesis of (−)-Macrolactin A
A R T I C L E S
Scheme 7
Scheme 8
Our initial strategy for installing the C7 stereocenter relied
upon successful addition of a chiral allenyl borane26 or,
alternatively, the use of an achiral allenyl stannane27 in the
presence of a chiral Lewis acid. Unfortunately, these methods
resulted in low conversion rates and scrambling of dienal 24.
Consequently, addition products possessing olefinic scrambling
were also observed. We turned then to more nucleophilic achiral
organometallics such as propargylmagnesium bromide or pro-
pargylzinc bromide. These reagents could be added cleanly to
the aldehyde and thus led naturally to the consideration of an
asymmetric modification. To our knowledge, there are no
documented cases for enantioselective additions of propargyl-
magnesium or propargylzinc species to aldehydes. In sharp
contrast, very high selectivities have been reported with the use
of divinyl or dialkyl organozinc reagents containing chiral
ligands.28 Specifically, Oppolzer28a reported the use of vinyl
organozinc reagents complexed with (+)-N-methylephedrine.
As an extension of Oppolzer’s methodology, the lithium salt
of (+)-N-methylephedrine was added to propargylzinc bromide
prior to addition of dienal 24. Modest asymmetric induction
(67:33, â/R) resulted in an inseparable mixture of alcohols 25.
The ratio and absolute sense of asymmetric induction were
determined by 1H NMR methods previously described by
Mosher et al.29 We were also able to verify that the stereose-
lectivity could be reversed by using the (-)-enantiomer of
N-methylephedrine. The ratio of diastereomers was within
experimental error, identical to (+)-N-methylephedrine, but with
the opposite sense of asymmetric induction. The alcohols were
protected as the methoxyisopropylidene acetal 26. The facility
with which this group could be removed was attractive not only
because it offered an opportunity to remove the acetonide in
the same operation, but because of the known sensitivities of
the Z/E-dienes. Final stage deprotection would require removal
in the presence of two Z/E dienes, one of which is in conjugation
with the lactone carbonyl. The MOM ether was also prepared,
but cleavage conditions presented difficulty in maintaining
stereochemical integrity of the Z/E-diene(s).
Scheme 9
workers have shown that heteroatoms can lead to deleterious
regioselectivity in the hydrostannation of alkynes, presumably
due to coordinative effects with palladium. They also showed
that significant improvements in regiocontrol could be achieved
by hydrostannation of the 1-bromoalkyne derivative under
palladium catalysis using 2 molar equiv of tri-n-butyltin
hydride.30 Indeed, this was the case with 27 (9:1, â/R).
Desilylation with TBAF at room temperature gave stannyl
alcohol 29 (Scheme 8). A Stille cross-coupling with methyl (Z)-
3-iodopropenoate31 further extended the linear chain to give the
macrocyclization precursor 30 (Scheme 9).
Saponification with methanolic KOH followed by esterifi-
cation using the Yonemitsu modification of the Yamaguchi
protocol32 for macrolactonization gave the protected macrocycle.
Deprotection with PPTS in wet methanol gave, after separation
with HPLC, (-)-1 and 7-epi-macrolactin A 30 (36% over four
steps). The structure of (-)-1 was confirmed by 2-D 1H NMR
and by comparison with authentic spectra.
Initial palladium-catalyzed hydrostannation of terminal alkyne
26 resulted in modest regiocontrol (7:3 â/R). Guibe´ and co-
In summary, our synthesis of macrolactin A is highly
convergent and efficient, allowing for the preparation of
(26) (a) Corey, E. J.; Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112, 878.
(b) Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am. Chem. Soc.
1982, 104, 7667.
(27) Keck, G. E.; Krishnamurthy, D.; Chen, X. Tetrahedron Lett. 1994, 35, 8323.
(28) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777. (b)
Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237.
(29) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
(30) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.
(31) Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1990, 1643.
(32) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. Tetrahedron 1990, 46,
4613.
9
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A R T I C L E S
Marino et al.
analogues with ease. The synthesis features a newly developed
1,3-diol synthon and the novel use of chiral sulfoxides. While
modest selectivity was obtained with the use of an asymmetric
propargylic zinc reagent, further study of this reaction could
lead to practical selectivities for formation of homopropargylic
alcohols.33 Finally, the first use of vinly tellurides in total
synthesis offers future possibilities in the development of new
organometallic approaches to Z/E-dienes.
Federal de Sa˜o Carlos, Brazil. We thank Professors Amos B.
Smith, III of the University of Pennsylvania and William Fenical
of the Scripps Institute of Oceanography for sending copies of
(-)-1 for comparison. We gratefully acknowledge CNPq/
FAPESP (Brazil) for financial support (fellowship to F.C.T.).
We appreciate assistance provided by Don Johnson of Pfizer
in the hydrogenation of ethyl 4-chloroacetoacetate for compound
6.
Acknowledgment. This work is dedicated to the memory of
Professor Jose´ Te´rcio Barbosa Ferreira of the Universidade
Supporting Information Available: Full experimental details
and spectral analyses for 1-3, 6-31 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(33) For recent and related examples, see also: (a) Denmark, S. E.; Wynn, T.
J. Am. Chem. Soc. 2001, 123, 6199. (b) El-Sayed, E.; Anand, N. K.;
Carreira, E. M. Org. Lett. 2001, 3, 3017.
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