With southern hemisphere 3.2 complete and the northern hemisphere 3.1 being constructed by Dr. Roberto Forrestieri, thoughts first turned to the steps necessary to complete a total synthesis (Scheme 3-1). The initial plan was to involve a Suzuki cross coupling between southern hemisphere 3.2 and a boronate (3.1) derived from the northern hemisphere. Such a
cross coupling would provide intermediate 3.3, based on the precedent of both the Furstner1 and
Paterson2 groups. Next, the installation of the C(23) and C(24) hydroxyl and methyl substituents
with control of stereochemistry would be required.
Scheme 3-1 Examination of proposed hemisphere union
Examination of intermediate 3.3, however, reveals an earlier underappreciated potential chemoselectivity problem - namely, the functionalization of the C(24)-C(25) olefin in the presence
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of unsaturation in the southern hemisphere [6,6]-spiroketal. A review of the previous strategies to install the C(24-25) stereodiad was not promising. Thus, the Paterson group used a hydroboration/oxidation sequence to chemo- and stereo-selectively functionalize the C(24)-C(25) olefin prior to spiroketal formation (Scheme 3-2 A). Such a reaction applied to 3.3 would almost certainly not be selective (Scheme 3-2 B), as the C(15)-C(16) olefin is expected to be both more sterically accessible and more electron rich. Indeed, it is perhaps as a result of this observation that the Paterson group elected to construct the southern hemisphere in a stepwise fashion.
Scheme 3-2 Problematic application of Paterson conditions to intermediate 3.3
The Furstner synthesis alternatively utilized a difficult hydrogenation of an exo-olefin in their spirastrellolide F synthesis (Scheme 3-3 A), which would not be suitable for intermediate 3.3 due to the more hindered nature of the internal C(23,24) olefin. In Furstner's synthesis, even the relatively unhindered exo olefin required very forcing conditions. The lack of oxygenation at C(23) in our proposed intermediate 3.3, also raised a chemoselectivity concern with the more sterically accessible C(15)-C(16) olefin (Scheme 3-3 B). Undoubtedly, similar concerns led the Furstner group to first construct spirastrellolide F (1.8), lacking unsaturation in the southern hemisphere, and to mask the corresponding olefin in their spirastrellolide A (1.2) synthesis as a dithiane.
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Scheme 3-3 Furstner approach to setting C(24)-C25) stereodiad
It quickly became clear that a new hemisphere coupling strategy would be required. We reasoned that masking and/or protecting the C(15)-C(16) olefin would be counterproductive, as spiroketal construction in 3.3 was the cornerstone of our southern hemisphere synthetic strategy. Instead, we sought a method that would permit functionalization of a C(24)-C(25) olefin chemoselectively. We were particularly intrigued by the possibility of using the C(23) hydroxyl, which we expected could be selectively deprotected, as a directing group for selective manipulation of the C(24)-C(25) olefin. Of the possible directed functionalizations, we chose the
Sharpless asymmetric epoxidation3 due to the mild conditions and broad functional group
compatibility. Although such a late stage oxidation is of considerably high risk, there are a large number of examples of the Shaprless epoxidation used in very complex settings. Figure 3-1
reveals a striking example from the Paterson synthesis of laulimalide A,4 in which a single olefin,
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Figure 3-1 Application of highly selective Sharpless asymmetric epoxidation to laulimalide
With these considerations in mind, a revised hemisphere union, as outlined in Scheme 3- 4, would be required. We reasoned that the C(25) methyl group could arise from the opening of an appropriate epoxide (3.12), which, in turn, would derive from a directed Sharpless asymmetric epoxidation of the appropriate allylic alcohol. In this manner, both the epoxidation and subsequent epoxide opening would be controlled by the C(23) hydroxyl. The requisite allylic alcohol (3.13) would result from a cross metathesis or ring closing metathesis of new northern and southern hemispheres 3.14 and 3.15.
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We further reasoned that the difficulties with olefin metathesis at the C(25)-C(26) bond encountered by Paterson and Furstner would not be as relevant in our system, as the site of metathesis was now two bonds removed from the bulky northern hemisphere. Finally, we were cognizant of the potential incompatibility of typical conditions for nucleophilic methylation of epoxides with such an advanced system. Nevertheless, we were encouraged by a number of
reports of such reactions in complex settings.5,6 In addition, we recognized that a number of
possible substrates were amenable to the proposed strategy. In particular, applying the epoxidation/ring opening sequence after macrocyclic ring closure would also be possible and could address potential pitfalls encountered in the acyclic case of 3.13, as the spirastrellolide
skeletons are well known to adapt distinctly different conformations upon macrocycle formation.1.2
To pursue such a revised hemisphere union plan, a new southern hemisphere target would be required, possessing a terminal olefin. As the terminal carbon atom of the olefin would be lost during the olefin metathesis upon hemisphere union, the revised target was envisioned to be a C(1)-C(23) fragment (i.e,, 3.15). Pleasingly, the retrosynthesis of this fragment, illustrated in Scheme 3-5, closely resembles our approach chosen for the previous southern hemisphere target (2.15, Scheme 2-6). Thus, spiroketalization and alkynylation leads back to aldehyde 3.17, which was used in the previous synthesis (i.e., 2.73), and a modified alkyne (3.18). Synthesis of alkyne 3.18 would thus be accomplished by a simple modification of the existing route, employing an Evans aldol reaction between the previously synthesized acylated oxazolidinone 3.19 (2.50 in Chapter 2) and acrolein.
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Scheme 3-5 Retrosynthetic analysis of modified southern hemisphere
In a forward direction (Scheme 3-6), the planned Evans aldol reaction proceeded smoothly. Given that acrolein is a commodity chemical, it could be used in large excess (4-10 equiv).
Scheme 3-6 Synthesis of revised alkyne 3.18
Employing these conditions, the desired aldol product 3.20 was isolated in 61% yield (91% brsm) as a single diastereomer. Importantly, the unreacted 3.19 could be readily recycled. Moreover, 10 grams of 3.20 could be readily prepared in one run. Conversion to the corresponding Weinreb amide and TES protection, followed by Grignard addition as before then led to ketone 3.22.
At the stage of the requisite diastereoselective reduction of 3.22, we observed a reduced yield due to an alternate pathway involving attack of the product hydroxyl group onto the alkyne moiety. The products of this reaction were tentatively assigned as a mixture of 3.24 and 3.25,
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which proved inseparable by column chromatography. However, after some optimization, the desired alcohol 3.23 could be obtained in a 61% yield by maintaining the reaction temperature below -60 °C. Pleasingly, methylation and removal o f the alkynyl TMS group completed the synthesis of the new alkyne fragment 3.18. Importantly, use of 3.18 as the new alkyne fragment removed the least efficient step in the previous synthesis, namely the preparation of aldehyde 2.48 (Scheme 2-10) for the key aldol reaction. As an added bonus, the lack of hindrance near the TES carbinol in 3.23 permitted the alkynyl TMS group to be removed in an excellent yield of 94% without affecting this previously sensitive TES. As a result, the new alkyne fragment 3.18 could now be prepared in 22% overall yield from 3.19 in 7 steps on multigram scale.
With the new alkyne fragment readily available, alkynylation with aldehyde 3.17 (Scheme 3-7), previously prepared in the synthesis of 2.15 (Scheme 2-19) was performed, resulting, as before, in a ~1.5:1 ratio of the diastereomeric alcohols, syn-3.26 and anti-3.26, (89% combined yield), which were readily separated by column chromatography (Scheme 3-7). Attempts to remove the benzoyl group as before, via DIBAL-H reduction, on the larger scales involved in this route led to erratic results, with incomplete conversion observed in most cases.
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Reoptimization of this process led to the identification and use of freshly prepared ethyl
magnesium bromide7 as the ideal reagent for the deprotection, proving reproducible 80-95%
yields of the desired diols syn-3.27 and anti-3.27. At this stage, we were able to confirm the
assignment of the stereochemistry present in these diols utilizing the method of Rychnovsky8 by
converting anti-3.27 to the corresponding bis acetonide 3.28, via treatment with dimethoxypropane in the presence of PPTS (Scheme 3-8). The presence of acetonide methyl peaks corresponding both to a syn acetonide (25, 25 ppm; C(9-11) diol) and an anti acetonide (19, 30 ppm; C(13-15) diol) suggested the stereochemistry as shown for 3.28 (Scheme 3-8). Finally, PMB removal employing excess DDQ (10 equiv) provided triols syn-3.29 and anti-3.29.
Scheme 3-8 Synthesis of revised spiroketalization precursors
The stage was now set for spiroketalization. Using the previously optimized conditions, anti-3.29 readily underwent cyclization to furnish the desired spiroketal 3.15 in 81% yield
(Scheme 3-9). This transformation completed the synthesis of the revised C(1)-C(23) southern hemsiphere fragment of spirastrellolide E in a longest linear sequence of 19 steps and an overall yield of 7.5%, a marked improvement over the route to 2.15 (Chapter 2), which had proceeded with an overall yield of 2% over the same number of steps. Moreover, with an improved route to alkyne fragment 3.17 available, the revised route proved to be significantly more scalable.
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Scheme 3-9 Synthesis of a revised southern hemisphere fragment for spirastrellolide E
The anti-3.29 isomer, on the other hand, again provided a different product under the same reaction conditions. This time, however, we discovered that performing the reaction in methanol, instead of THF, permitted the isolation of spectroscopically pure material after simple filtration through a pad of silica gel to remove the gold catalyst. The pure sample, in turn
permitted application of a series of detailed 1D (1H, 13C NMR and DEPT) and 2D (COSY, HSQC,
NOESY, TOCSY) NMR studies. With NMR interpretation unhampered by extraneous signals, the structure of the byproduct could now be assigned as 3.30 (Figure 3-2).
Figure 3-2 Product from attempted spiroketalization of syn-3.29