Alternaric acid: Formal synthesis and related studies

Article abstract of DOI:10.3762/bjoc.9.19

A silyl glyoxylate three-component-coupling methodology has been exploited to achieve a formal synthesis, an analogue to an intermediate in a distinct formal synthetic route, and a third (unique) approach to the natural product alternaric acid. Highlighte

Full text of DOI:10.3762/bjoc.9.19

Alternaric acid: formal synthesis and related studies
Michael C. Slade and Jeffrey S. Johnson*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 166–172.
Caudill Laboratories, Department of Chemistry, University of North
Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
doi:10.3762/bjoc.9.19
Received: 24 October 2012
Accepted: 20 December 2012
Published: 24 January 2013
Email:
Jeffrey S. Johnson* - jsj@unc.edu
* Corresponding author
This article is part of the Thematic Series "Creating complexity".
Guest Editor: D. Craig
Keywords:
formal synthesis; multicomponent coupling; natural products; silyl
glyoxylates
© 2013 Slade and Johnson; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A silyl glyoxylate three-component-coupling methodology has been exploited to achieve a formal synthesis, an analogue to an
intermediate in a distinct formal synthetic route, and a third (unique) approach to the natural product alternaric acid. Highlighted in
this study is the versatility of silyl glyoxylates to engage a variety of nucleophile and electrophile pairs to provide wide latitude in
the approach to complex molecule synthesis.
Introduction
The rapid development of molecular complexity from simple cally dense core of the molecule; the potential application of
starting materials is an important goal in modern synthetic silyl glyoxylate technology emerged as an attractive starting
organic chemistry. In this context, streamlined one-pot transfor- point for synthetic planning (Scheme 1B). This paper summa-
mations, cascade reactions, and multicomponent couplings have rizes our synthetic work in this arena, which culminated in a
emerged as enabling tools for the synthesis of complex mole- formal synthesis, an analogue of another formal synthesis, and a
cules [1,2]. Our laboratory [3-16] and others have developed unique approach to the target; each of the routes was enabled by
[17] and employed [18,19] silyl glyoxylates 1 in a variety of distinct coupling partners.
synthetic endeavors, both in natural-product synthesis and syn-
thetic methodologies [20]. Key to their use in a variety of Alternaric acid is a particularly interesting target to demon-
contexts is the ability of silyl glyoxylates to function as linchpin strate the utility of silyl glyoxylates, as it has been the subject of
synthons for geminal coupling of nucleophile/electrophile pairs one total synthesis [24], one formal synthesis [25], and a poten-
at a glycolic acid subunit (Scheme 1A), which allows the rapid tial application of an asymmetric glycolate aldol methodology
build-up of molecular complexity. Alternaric acid (2) [21-23] is [26]. These precedents serve as fruitful comparison points for
an antifungal and phytotoxic natural product, which bears a application of a silyl glyoxylate three-component coupling
substituted glycolic acid in the functionally and stereochemi- methodology. Scheme 2 highlights three potential avenues
166

Beilstein J. Org. Chem. 2013, 9, 166–172.
Scheme 1: (A) Silyl glyoxylates as versatile reagents for three-component coupling reactions: representative nucleophiles and electrophiles.
(B) Alternaric acid as a potential application of a silyl glyoxylate-enabled three-component coupling reaction.
Scheme 2: Potential applications of silyl glyoxylate couplings and precedent synthetic intermediates toward the synthesis of alternaric acid.
toward the natural product and their precedents, by using the facial selectivity was rather poor, i.e., approximately 1.7:1,
readily available (S)-2-methylbutanal (3) [27] and silyl glyoxy- regardless of nucleophile, counterion, solvent, and temperature.
lates 1 as two of the three key components for a coupling Brief optimization efforts for each nucleophile thus focused on
reaction.
maximizing the coupling efficiency and syn-/anti-aldol selec-
tivity (see Supporting Information File 1).
Results and Discussion
Synthetic studies were initiated to explore paths a and b in The optimal conditions for use of a vinyl nucleophile involved
Scheme 2, given the perceived rapidity with which the known addition of a solution of vinylmagnesium bromide (4) and
intermediates could be intercepted after the proposed three- (−)-sparteine [31] in toluene to a solution of the tert-butyl silyl
component coupling reactions. These initial studies revealed a glyoxylate 1a and (S)-2-methylbutanal (3) in toluene at −78 °C
limitation to this approach, inherent in the use of aldehyde 3 as followed by warming to room temperature, which provided the
a coupling partner: inherently poor Felkin–Anh facial selec- three-component-coupling product 5 with excellent (>20:1)
tivity with respect to the aldehyde electrophile due to minor dif- syn-/anti-aldol selectivity in 65% yield (Scheme 3). Ichihara’s
ferentiation between the Et/Me groups [28-30]. In all cases, the aldehyde intermediate could be intercepted in three additional
167

Beilstein J. Org. Chem. 2013, 9, 166–172.
Scheme 3: Three-component coupling with a vinyl nucleophile and elaboration to Ichihara’s aldehyde.
steps, in high overall yield. Simultaneous cleavage of the silyl (11) in THF to a THF solution of benzyl silyl glyoxylate 1b and
ether and transesterification from the tert-butyl to the methyl (S)-2-methylbutanal (3) at 0 °C followed by warming to room
ester in 6 was effected by warming in acidic methanol. Subse- temperature (Scheme 5). In the event, the three-component
quent acetonide formation provided 7, and ozonolysis afforded coupling product 12 was in 50% combined yield of all four
Ichihara’s aldehyde 8 (Scheme 3).
possible diastereomers: 3.6:1 syn-/anti-selectivity and ~1.7:1
facial selectivity were observed. Thus, under these conditions
Interception of this intermediate thus constituted a formal syn- both the control of enolate geometry as well as facial selec-
thesis; the precedent for the C8–C9 olefination involved a clas- tivity with respect to the aldehyde were incomplete. The four
sical, three-step Julia olefination sequence [24]. To demon- diastereomers could only be separated into syn/anti sets; within
strate proof-of-concept for a more step-efficient endgame, test each set, the Felkin/anti-Felkin diastereomers could not be sep-
substrates were prepared for exploration of a modified Julia arated.
olefination [32]. As shown in Scheme 4, the phenyltetrazole
heteroaromatic core in sulfones 9a and 9b provided excellent As with three-component coupling product 5, advancement of
E-/Z- selectivity for formation of the C8–C9 olefin under intermediate 12 proved straightforward (Scheme 5). Deprotec-
typical modified Julia conditions with no optimization tion of the silyl ether with TBAF afforded diol 13, which is a
necessary. In particular, the vinyl bromide functional benzyl ester analogue of one of Trost’s substrates employed in
handle in 10b provides a potential avenue for elaboration to the the ruthenium-catalyzed Alder–ene reaction [25]. It too proved
natural product.
to be a successful substrate for the reaction with alkyne 14,
affording the 1,4-diene product 15 in 52% yield. This sequence
With the promise of the approach thus demonstrated involving thus demonstrated a second avenue for successful exploitation
the use of the vinyl nucleophile, attention shifted toward explo- of a silyl glyoxylate coupling methodology to achieve a step-
ration of the allyl nucleophile. The best conditions for the use of efficient approach toward the assembly of the carbon skeleton
an allyl nucleophile involved the addition of allylzinc bromide of alternaric acid.
Scheme 4: Modified Julia olefination as a step-efficient alternative endgame strategy.
168

Beilstein J. Org. Chem. 2013, 9, 166–172.
Scheme 5: Three-component coupling with an allyl nucleophile and demonstration of successful ruthenium-catalyzed Alder–ene approach.
The two approaches described above both highlighted an deprotection in any silyl glyoxylate-based approach, this modi-
important limitation to the use of (S)-2-methylbutanal (3) fication would represent a relatively minor departure from
as the third component in the silyl glyoxylate-based three- ideality in the form of additional concession steps [35]. Alter-
component coupling reaction: while this aldehyde directly natively, modification of the aldehyde partner, as in general-
affords the substructure of the natural product target, it is ized type 16, was also considered. For this purpose, any stereo-
unable to adequately control the facial selectivity of the controlling element (Ω or Ψ in aldehyde types 16a and 16b, res-
approach of the glycolate enolate revealed after nucleophile pectively) employed should meet the additional requirement
addition/[1,2]-Brook [33] rearrangement. Moreover, attempts that it be easily converted to a simple ethyl group to minimize
to achieve separation of the resultant diastereomers at the number of concession steps.
all synthetic intermediates in these two routes were un-
successful. Thus, attention shifted to address the stereo- The auxiliary approach using silyl glyoxylates 1c ([Si] = TES or
chemical issue.
TBS, Scheme 6) proved to be suboptimal: despite the successful
formation of the desired three-component coupling product,
Various approaches were considered to achieve a higher level yields were low and poor stereochemical control was
of stereoselection in the three-component coupling reaction, observed. Likewise, even the extreme steric demand of the
which are summarized in Scheme 6 [34]. In light of the elegant tris(trimethylsilyl) group in aldehyde 16aa was insufficient for
precedent for overriding the moderate substrate bias from (S)-2- adequate stereocontrol in the three-component coupling reaction
methylbutanal (3) [26], auxiliary modification of the silyl [34]. An additional branch point in the carbon backbone, such
glyoxylate structure to generalized type 1c could be envisioned. as in 16b, was deemed necessary. The 1,3-dithiane group in
As hydrolysis of an ester would be required as a late-stage aldehyde 16ba was conceived as a promising candidate for a
Scheme 6: Approaches considered to address the stereochemical issue.
169

Beilstein J. Org. Chem. 2013, 9, 166–172.
stereocontrolling element due to its large size and the wealth of coupling reaction (Scheme 8). It began from the known allylic
precedents for single-step desulfurization to alkanes [36-40]. alcohol 21 [46], which was acetylated to afford ester 22 as
The racemic synthesis of the requisite aldehyde proved straight- prelude for reaction as a π-allyl electrophile with the Refor-
forward (see Supporting Information File 1). Most importantly, matsky reagent 23 derived from tert-butyl bromoacetate. The
in initial three-component coupling reactions with vinyl nucleo- TMS-alkyne in 24 was deprotected with buffered TBAF to
phile 4 and silyl glyoxylate 1a under previously optimized afford free alkyne 25, and the vinyl iodide 26 was generated by
conditions, high efficiency was achieved along with excellent hydrozirconation/iodination of the free alkyne with Schwartz’s
(>20:1) stereochemical control for the formation of three- reagent [47]. The vinyl nucleophile 27 could be generated by
component-coupling product 17 (Scheme 7) [41-44]. To verify Knochel’s Mg/I exchange [48] and employed successfully in
that the dithiane was acting in the desired fashion, and to rule the three-component-coupling reaction with silyl glyoxylate 1a
out chelation from one of the Lewis basic sulfur atoms, derivati- and aldehyde 16ba to assemble 28, which contains the bulk of
zation to a lactone was carried out. The dithiane was cleaved to the carbon skeleton of alternaric acid. Remarkably, this highly
the ketone 18, which underwent a 1,3-syn-selective reduction convergent coupling allows the majority of the carbon back-
[45]. The resultant diol 19 was subjected to acidic conditions to bone of the natural product to be assembled in a single
effect cleavage of the tert-butyl ester and lactonization to afford complexity-building step.
20. The NOESY and coupling-constant data of 20 was consis-
tent with the role of the dithiane in 16ba as a nonchelating RL With this gratifying result, a third distinct route to alternaric
group that led to Felkin selectivity in the three-component acid was enabled. Most importantly, this provides the first
coupling reaction.
example of such a highly functionalized nucleophile being used
in a silyl glyoxylate based three-component coupling reaction.
The complete diastereochemical control exerted by the dithiane Remaining tasks for the complete formation of the natural prod-
moiety of the aldehyde 16ba provided the impetus for exploring uct include desulfurization [49], deprotection [50], and
the use of a functionalized vinyl nucleophile in the three- appendage of the pyrone moiety [24].
component coupling reaction. Use of a more complex nucleo-
phile would maintain the convergence of the overall synthesis, Conclusion
which was deemed important because (1) the route to the alde- In conclusion, we have described the application of silyl
hyde component was becoming more involved; and (2) one or glyoxylate three-component-coupling reactions as the central
more additional steps for the removal of the directing group feature of three distinct approaches to the total synthesis of
would be required. Thus, we developed a synthesis of a nucleo- alternaric acid. By judicious choice of coupling partner and
phile that would allow the vast majority of the alternaric acid reaction conditions, it has been possible to achieve a formal
carbon skeleton to be installed through the three-component synthesis, an analogous formal synthesis via an alternative
Scheme 7: Use of a dithiane moiety to excert stereochemical control in the three-component coupling reaction and supporting evidence for its nature
as a nonchelating RL.
170

Beilstein J. Org. Chem. 2013, 9, 166–172.
Scheme 8: Synthesis of a vinyl iodide for nucleophile generation and its use in a three-component coupling reaction.
References
route, and significant progress toward a third distinct route
reliant on a highly functionalized nucleophile/electrophile
combination for the construction of the majority of the natural
product in a single step. In particular, this underscores the
unique utility of silyl glyoxylates to serve as crucial linchpins
for the coupling of a variety of nucleophile/electrophile pairs at
a glycolic acid junction for the rapid development of molecular
complexity.
1. Nicolaou, K. C.; Hale, C. R. H.; Nilewski, C.; Ioannidou, H. A.
Chem. Soc. Rev. 2012, 41, 5185–5238. doi:10.1039/c2cs35116a
2. Rapid complexity generation in natural product total synthesis. Chem.
Soc. Rev. 2009, 38, 2969–3276. doi:10.1039/b920767h
See the thematic issue for a recent compilation of reviews on this topic
in the context of natural-products synthesis.
3. Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
6170–6171. doi:10.1021/ja043884l
4. Linghu, X.; Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006,
128, 9302–9303. doi:10.1021/ja062637+
5. Nicewicz, D. A.; Brétéché, G.; Johnson, J. S.; Bryan, C.; Lautens, M.
Org. Synth. 2008, 85, 278–286.
Supporting Information
6. Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 17281–17283. doi:10.1021/ja808347q
7. Greszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827–830.
doi:10.1021/ol802828d
Contains additional tables and schemes for the
three-component coupling reactions and approaches to
address the stereochemical problem. Also contains
experimental procedures, characterization, and spectral
data.
8. Greszler, S. N.; Johnson, J. S. Angew. Chem., Int. Ed. 2009, 48,
3689–3691. doi:10.1002/anie.200900215
9. Schmitt, D. C.; Johnson, J. S. Org. Lett. 2010, 12, 944–947.
doi:10.1021/ol9029353
Supporting Information File 1
Additional data.
10.Steward, K. M.; Johnson, J. S. Org. Lett. 2010, 12, 2864–2867.
doi:10.1021/ol100996w
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-19-S1.pdf]
11.Boyce, G. R.; Johnson, J. S. Angew. Chem., Int. Ed. 2010, 49,
8930–8933. doi:10.1002/anie.201003470
12.Greszler, S. N.; Malinowski, J. T.; Johnson, J. S. J. Am. Chem. Soc.
2010, 132, 17393–17395. doi:10.1021/ja108848d
13.Greszler, S. N.; Malinowski, J. T.; Johnson, J. S. Org. Lett. 2011, 13,
3206–3209. doi:10.1021/ol2011192
Acknowledgements
The project described was supported by Award R01 GM084927
from the National Institute of General Medical Sciences. We
thank Rebecca Cuellar for early exploratory studies and Justin
Malinowski and Michael Corbett (UNC) for acquiring mass-
spectral data.
14.Schmitt, D. C.; Lam, L.; Johnson, J. S. Org. Lett. 2011, 13, 5136–5139.
doi:10.1021/ol202002r
15.Boyce, G. R.; Liu, S.; Johnson, J. S. Org. Lett. 2012, 14, 652–655.
doi:10.1021/ol2033527
171

Beilstein J. Org. Chem. 2013, 9, 166–172.
16.Schmitt, D. C.; Malow, E. J.; Johnson, J. S. J. Org. Chem. 2012, 77,
3246–3251. doi:10.1021/jo202679u
41.Aldehyde 16ba has previously been used in aldol reactions; no
comment on the diastereoselectivity was made, likely because it was
immaterial in those applications (see [42,43]).
17.Bolm, C.; Kasyan, A.; Heider, P.; Saladin, S.; Drauz, K.; Günther, K.;
Wagner, C. Org. Lett. 2002, 4, 2265–2267. doi:10.1021/ol025911n
18.Lettan, R. B.; Galliford, C. V.; Woodward, C. C.; Scheidt, K. A.
J. Am. Chem. Soc. 2009, 131, 8805–8814. doi:10.1021/ja808811u
19.Yao, M.; Lu, C. D. Org. Lett. 2011, 13, 2782–2785.
doi:10.1021/ol201029b
42.Kim, H.; Baker, J. B.; Lee, S.-U.; Park, Y.; Bolduc, K. L.; Park, H.-B.;
Dickens, M. G.; Lee, D.-S.; Kim, Y.; Kim, S. H.; Hong, J.
J. Am. Chem. Soc. 2009, 131, 3192–3194. doi:10.1021/ja8101192
43.Kim, H.; Baker, J. B.; Park, Y.; Park, H. B.; DeArmond, P. D.;
Kim, S. H.; Fitzgerald, M. C.; Lee, D.-S.; Hong, J. Chem.–Asian J.
2010, 5, 1902–1910. doi:10.1002/asia.201000147
20.Boyce, G. R.; Greszler, S. N.; Johnson, J. S.; Linghu, X.;
Malinowski, J. T.; Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.;
Steward, K. M. J. Org. Chem. 2012, 77, 4503–4515.
doi:10.1021/jo300184h
44.Ward, D. E.; Kazemeini, A. J. Org. Chem. 2012, 77, 10789–10803.
doi:10.1021/jo302142v
While this manuscript was in review, a thorough study of the
stereochemical outcomes using structurally related aldehydes was
reported.
Perspective article.
21.Brian, P. W.; Curtis, P. J.; Hemming, H. G.; Unwin, C. H.; Wright, J. M.
Nature 1949, 164, 534. doi:10.1038/164534a0
45.Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 16, 1923–1926.
doi:10.1246/cl.1987.1923
22.Brian, P. W.; Curtis, P. J.; Hemming, H. G.; Jefferys, E. G.;
Unwin, C. H.; Wright, J. M. J. Gen. Microbiol. 1951, 5, 619–632.
doi:10.1099/00221287-5-4-619
46.Renaud, J.-L.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1999, 40,
5015–5018. doi:10.1016/S0040-4039(99)00981-8
23.Bartels-Keith, J. R. J. Chem. Soc. 1960, 1662–1665.
doi:10.1039/JR9600001662
47.Reichard, H. A.; Rieger, J. C.; Micalizio, G. C. Angew. Chem., Int. Ed.
2008, 47, 7837–7840. doi:10.1002/anie.200803031
24.Tabuchi, H.; Hamamoto, T.; Miki, S.; Tejima, T.; Ichihara, A.
J. Org. Chem. 1994, 59, 4749–4759. doi:10.1021/jo00096a016
25.Trost, B. M.; Probst, G. D.; Schoop, A. J. Am. Chem. Soc. 1998, 120,
9228–9236. doi:10.1021/ja981540n
48.Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215–4217.
doi:10.1021/ol048363h
49.Initial attempts to effect this transformation in a model system have
demonstrated that this may not be as straightforward as anticipated.
See Supporting Information File 1 for details.
26.Giampietro, N. C.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2009,
131, 12556–12557. doi:10.1021/ja905930s
27.Anelli, P. L.; Montanari, F.; Quici, S.; Nonoshita, K.; Yamamot, H.
Org. Synth. 1990, 69, 212.
50.Likewise, this may prove more difficult than anticipated; acid-promoted
hydrolysis of the tert-butyl esters and silyl ether was planned, due to
the success of such a transformation with the simpler substrate 5, as in
Scheme 3. However, substrate 28 tends to decompose when treated
under a variety of acidic conditions.
28.Our results are consistent with the additions of nucleophiles to 3 (cf.
[24-26]). For rare, successful examples of Me/Et differentiation, see
[29,30].
29.Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C.
J. Am. Chem. Soc. 1997, 119, 7893–7894. doi:10.1021/ja971521y
30.Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
6496–6502. doi:10.1021/ja0108584
License and Terms
31.The precise role of the (−)-sparteine is uncertain at this time. It is
possible that the Lewis basic nitrogens chelate the magnesium,
facilitating the reversibility of the aldolization step leading to high
syn-selectivity. See [20], footnote 42.
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
32.Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
doi:10.1039/B208078H
33.Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84.
doi:10.1021/ar50075a003
34.The results of efforts with silylglyoxylates 1c, and other specific
examples for the identities of Ω and Ψ, were also pursued. See
Supporting Information File 1 for additional details.
35.Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657–4673.
doi:10.1021/jo1006812
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
36.Yang, T.-K.; Lee, D.-S.; Haas, J. Raney Nickel. e-EROS Encyclopedia
of Reagents for Organic Synthesis; John Wiley & Sons: New York, N.
Y., 2006. doi:10.1002/047084289X.rr001.pub2
doi:10.3762/bjoc.9.19
37.Back, T. G.; Baron, D. L.; Yang, K. J. Org. Chem. 1993, 58,
2407–2413. doi:10.1021/jo00061a011
38.Chan, M. C.; Cheng, K. M.; Ho, K. M.; Ng, C. T.; Yam, T. M.;
Wang, B. S. L.; Luh, T. Y. J. Org. Chem. 1988, 53, 4466–4471.
doi:10.1021/jo00254a009
39.Becker, S.; Fort, Y.; Vanderesse, R.; Caubere, P. Tetrahedron Lett.
1988, 29, 2963–2966. doi:10.1016/0040-4039(88)85058-5
40.Becker, S.; Fort, Y.; Caubere, P. J. Org. Chem. 1990, 55, 6194–6198.
doi:10.1021/jo00312a029
172