Total synthesis of natural (?)- and unnatural (+)-Melearoride A

Article abstract of DOI:10.1016/j.tetlet.2019.02.006

This communication details the first total synthesis of the 13-membered macrolide, (?)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.

Full text of DOI:10.1016/j.tetlet.2019.02.006

Accepted Manuscript
Total synthesis of natural (-)- and unnatural (+)-Melearoride A
Carson W. Reed, Mark G. Fulton, Kellie D. Nance, Craig W. Lindsley
PII:
S0040-4039(19)30114-5
https://doi.org/10.1016/j.tetlet.2019.02.006
TETL 50600
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
10 January 2019
1 February 2019
2 February 2019
Please cite this article as: Reed, C.W., Fulton, M.G., Nance, K.D., Lindsley, C.W., Total synthesis of natural (-)-
and unnatural (+)-Melearoride A, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.006
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Total synthesis of natural (-)- and unnatural (+)-
Melearoride A
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Carson W. Reed, Mark G. Fulton, Kellie D. Nance and Craig W. Lindsley

1
Tetrahedron Letters
Total synthesis of natural (-)- and unnatural (+)-Melearoride A
Carson W. Reed,¥ Mark G. Fulton,¥ Kellie D. Nance¥ and Craig W. Lindsley¥,ǂ*
¥Department of Chemistry, Vanderbilt University, Nashville, TN 37232-6600, U.S.A.
ǂDepartment of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232-6600, U.S.A.
ARTICLE INFO
ABSTRACT
This communication details the first total synthesis of the 13-membered macrolide, (-)-
Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step
synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple
opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a
cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close
the 13-membered macrocyclic core.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Melearoride A
total synthesis
macrolides
2019 Elsevier Ltd. All rights reserved.
asymmetric alkylation
Natural products can serve as novel chemical entities to
initiate highly productive tool compound and lead optimization
campaigns. Recently, total synthesis campaigns in our lab have
led to the discovery of novel biological activity for a variety of
natural products, and in instances, unnatural analogs displayed
superior bioactivity.1 (-)-Melearoride A (1a) (Figure 1) was first
isolated in 2016 from a fermentation broth of Penicillum
meleagrinum var. viridiflavum and shown to have synergistic
activity with fluconazole against azole-resistant Candida
albicans.2 This 13-membered macrocyclic natural product
belongs to a family of related natural products 3-7 (exemplified
by PF1163A (3) and PF1163B (4)), whose syntheses have been
previously reported.3-7 These first-generation synthetic
approaches rely heavily on the use of diastereoselective additions
into functionalized aldehydes3-4 or lactals,5 or Sharpless kinetic
resolution techniques6 to set the stereochemistry at the C9
position and, with the exception of Bouazza,4 involve lengthy
synthetic routes. Given both that the synthesis of (-)-Melearoride
A (1a) has yet to be accomplished and our desire to merge total
synthesis with opportunities for medicinal chemistry
optimization, our goal was to develop a concise, modular
synthetic route that would be amenable for analog development.
Ideally, we sought a route that would enable control of the
substituents and stereochemistry of the alkyl groups on C6 and
C9, the size of the macrocycle, and with late stage diversity
opportunities for the phenolic alkyl group. The key features of
this synthesis include Evans asymmetric alkylation, chiral
epoxide opening using functionalized higher order
cyanocuprates, ring-closing metathesis to form the 13-membered
macrocycle, and late stage O-alkylation utilizing Mitsunobu
conditions. In order to show the utility of this method for analog
development, we synthesized not only natural (-)-Melearoride A
(1a), but also unnatural (+)-Melearoride A (1b) in 13 steps and
with 11 step Longest Linear Sequence (LLS) in good overall
yields.
Figure 1. Structures of natural (-)-Melearoride A (1a), unnatural (+)-
Melearoride A (1b), Melearoride B (2) and early members of this family of
macrolide natural products PF1163A (3), PF1163B (4), PF1163D (5),
PF1163H (6) and PF1163F (7).2

2
Tetrahedron
Figure 2. Retrosynthesis of (-)-1a. Five key bond disconnections lead to
readily available intermediates 8-12, with chirality derived from chiral pool
molecules.
Figure 2 highlights our retrosynthetic analysis for 1a, with
five key bond disconnects leading to five simple intermediates 8-
12, all of which are commercial (eg., 8, 9, 10) and/or readily
derived from chiral pool molecules (eg., 11 and 12). Based on
this strategy, the ability to readily access unnatural (+)-1b by
virtue of employing the opposite stereochemistry of
intermediates 8, 11, and 12 was clear, and thus, two parallel
synthesis campaigns were initiated.
Scheme 2. Synthesis of chiral tosylates 12a-b. Reagents and conditions: (a)
n-BuLi, propionic anhydride, THF, -78 °C to rt, 1h, 89-94%; (b) NaHMDS,
allyl iodide, THF, -78 °C, 6h, 58-61%; (c) LiBH4, EtOH, 0 °C to rt, 16h, 54-
72%; (d) TsCl, pyr., CHCl3, 0 °C to rt, 16h, 69-80%.
Following the method of Lipshutz,14 transmetalation of the
resulting alkyl lithium reagents with lithium 2-thienyl
cyanocuprate afforded functionalized higher order cuprates,
which were competent in opening epoxides 11a-b. With the
desired C7-C8 bond formed, esterification of alcohols 20a-b with
commercially available acids (S)-8a and (R)-8b was
accomplished using Yamaguchi conditions. Overall, this three-
step transformation afforded esters 21a and 21b in good yields
(31-47% over three steps) and only required one formal
chromatographic operation.
The key C8-C14 epoxide intermediate 11 was readily
prepared in two steps (Scheme 1). Following the precedent of
Moriarty and Kulkarni,8-9 commercial chiral pool (R)- and (S)-
epichlorohydrin 13a and 13b, respectively, were treated with n-
butyl magnesium chloride and catalytic copper iodide to afford
the -chloro alcohols (R)-14a and (S)-14b in yields ranging from
66-77%. Treatment with NaOH in Et2O provides the requisite
chiral epoxides 11a (to access (-)-1a) and 11b (to access (+)-1b)
in good yields.
With all the stereocenters set, the final steps toward the
synthesis of 1a and 1b could be accomplished. Boc-deprotection
of 21a-b using TFA in CH2Cl2 followed by PyBroP-mediated
amide coupling with vinylacetic acid 9 led to the formation of
amides 22a and 22b in 82-89% yield (Scheme 4). In order to
avoid undesired chelation and catalyst sequestration due to the
presence of the β-γ unsaturated amide in 22a-b,15 a Lewis acid
assisted ring closing-metathesis (RCM) reaction was determined
to be most suitable for forming the desired 13-membered
macrocyclic core.16 Indeed, the use of Grubbs II and Ti(OiPr)4 in
the RCM followed by subsequent hydrogenation gave desired
phenols 23a-b in 60-65% yield over two steps.
Scheme 1. Synthesis of chiral expoxides 11a-b. Reagents and conditions:
(a) n-BuMgCl, cat. CuI, THF, -78 °C to 0 °C, 3h, 66-77%; (b) NaOH, Et2O,
rt, 3h, 70-86%.
Chiral tosylates 12a and 12b were synthesized per the
methods of Jouillié and Molander (Scheme 2).10-11 Upon
acylation of commercial oxazolidinones (S)-15a and (R)-15b
under standard conditions,12-13 an Evans asymmetric allylation
was utilized to synthesize oxazolidinones 17a and 17b in good
yields with ~20:1 d.r. Reduction with lithium borohydride
provided alcohols (R)-18a and (S)-18b in yields ranging from 54-
72%. Subsequent treatment with p-toluenesulfonyl chloride and
pyridine afforded (R)-12a (en route to 1a) and (S)-12b (en route
to 1b) in good yields (69-80%).
With requisite fragments 11a-b and 12a-b in hand, a method
was needed to unite both fragments and form the crucial C7-C8
bond. To achieve this synthetic transformation, we envisioned
that organocuprate reagents derived from 12a-b would be
satisfactory in opening epoxides 11a-b to form the required C7-
C8 bond (Scheme 3). SN2 displacement of tosylates 12a-b with
lithium iodide in DMA afforded alkyl iodides 19a-b which
underwent lithium-halogen exchange with t-BuLi smoothly.
Scheme 3. Synthesis of esters 21a-b. Reagents and conditions: (a) LiI,
DMA, 80 °C, 2h; (b) t-BuLi, lithium 2-thienylcyanocuprate, 11a or 11b,

3
Et2O, THF, -78 °C to rt, 5h; (c) 2,4,6-trichlorobenzoyl chloride, DMAP, Et3N,
10. Hansen, D. B., Starr, ML., Tolstoy, N., Joullié, M. M.;
8a or 8b, toluene, rt, 16h, (31-47% over three steps).
Tetrahedron: Asymmetry 2005, 16, 3623-3627.
11. Pack, S. K., Molander, G. A.; J. Org. Chem. 2003, 68, 9214-9220.
12. Gage, J. R., Evans, D. A.; Org. Synth. 1990, 68, 83-91.
13. Matousek, V., Togni, A., Bizet, V., Cahard, D.; Org. Lett. 2011,
13, 5762-5765.
14. Lipshutz, B. H., Koerner, M., Parker, D. A.; Tetrahedron Lett.
1987, 28, 945-948.
15. Fürstner, A., Langemann, K.; J. Am. Chem. Soc. 1997, 119, 9130-
9136.
16. Yang, Q., Xiao, W-J., Yu, Z.; Org. Lett. 2005, 7, 871-874.
AUTHOR INFORMATION
Corresponding Author
* E-mail: craig.lindsley@vanderbilt.edu
Phone: 615-322-8700, fax: 615-343-3088
Scheme 4. Synthesis of natural (-)-Melearoride A 1a and unnatural (+)-
Melearoride A 1b. Reagents and conditions: (a) i. TFA, CH2Cl2, 0 °C to rt,
1h, ii. PyBroP, vinylacetic acid (9), N,N-diisopropylethylamine, CH2Cl2, 0 °C
to rt, 3h, 82-89%; (b) Grubbs CatalystTM 2nd Generation, Ti(OiPr)4, toluene,
90 °C, 7h; (c) H2, Pd/C, EtOAc, rt, 16h, (60-65% over two steps); (d) DIAD,
PPh3, 3-methyl-2-buten-1-ol (10), THF, 0 °C to rt, 2h, 69-72%.
Lastly, O-alkylation of phenol 23a and 23b using alcohol 10
under Mitsunobu conditions yielded natural (-)-Melearoride A
(1a) and unnatural (+)-Melearoride A (1b) in 69-72% (4.3% and
1.0% overall yields for 1a and 1b, respectively).
In conclusion, we have presented the first total synthesis of
both (-)-Melearoride A (1a) and (+)-Melearoride A (1b) in good
overall yields. In addition, our modular synthetic approach
enables facile analog development, which will prove useful for
the future exploration of antifungal SAR around related
macrocyclic congeners.
Acknowledgments
Financial support from the Warren Family and Foundation is
gratefully acknowledged and for establishing the William K.
Warren, Jr. Chair in Medicine.
References and notes
1. Hahn, K. N.; Fadeyi, O. O.; Cho, H. P.; Lindsley, C. W.;
Tetrahedron Lett. 2012, 53, 3577-3580.
2. Okabe, M.; Sugita, T.; Kinoshita, K.; Koyama, K. J. Nat. Prod.
2016, 79, 1208-1212.
3. Tatsuta, K., Takano, S., Ikeda, Y., Nakano, S., Miyazaki, S.; J.
Antibiot. 1999, 52, 1146-1151.
4. Bouazza, F.; Renoux, B., Bachmann, C., Gesson, JP.; Org. Lett.
2003, 5, 4049-4052.
5. Kumar, H., Reddy, A. S., Subba Reddy, B.V.; Tetrahedron Lett.
2014, 55, 1519-1522.
6. Krishna, P. R., Srinivas, P.; Tetrahedron: Asymmetry 2012, 23,
769-774.
7. Yadav, J. S., Venkatesh, M., Thrimurtulu, N., Prasad, A. R.;
Synlett 2010, 8, 1255-1259.
8. Moriarty, R. M.; Rani, N., Enache, L. A., Rao, M. S., Batra, H.,
Guo, L., Penmasta, R. A., Staszewski, J. P., Tuladhar, S. M.,
Prakash, O., Crich, D., Hirtopeanu, A., Gilardi, R.; J. Org. Chem.
2004, 69, 1890-1902.
9. Jana, S., Sarpe, V. A., Kulkarni, S. S.; Org. Lett. 2018, 20, 6938-
6942.

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Tetrahedron
Highlights



First total synthesis of (-)-melearoride A
Total synthesis of (+)-melearoride A
A concise 13 step synthesis from chiral pool
starting materials

High yielding RCM to close the 13-membered
macrocycle