Undaunted, we reasoned that the use of a substrate possessing differential protection at the C(13), C(21) and C(22) hydroxyls would be more amenable to reaction optimization due to the possibility of isolating a triol spiroketalization precursor 2.71, which would not require any additional functional group manipulations during spiroketalization (Scheme 2-15).
Scheme 2-15 Revised strategy for spiroketalization
We therefore chose 2.71 as our new target (Scheme 2-16). Notably, in addition to the differential protection at C(13) and C(21), we chose to return to TBS protection at the C(9) and C(11) carbinols due to the aforementioned difficulties expected with selective MOM group removal at the late stages of the synthesis (vide supra).
Analysis of 2.71 is illustrated in Scheme 2-16. Spiroketalization and alkynylation were still envisioned as the end game, now requiring aldehyde 2.72. Importantly, this aldehyde could be constructed from the identical ARC components as our original intermediates by simply changing the order of addition, followed by dithiane removal and stereoselective reduction of the resulting
ketone. This tactic serves as another illustration of the remarkable flexibility and utility of the ARC union protocol.
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Scheme 2-16 Revised retrosynthetic analysis
In the forward direction, ARC union with inverted order of addition proceed equally well under the conditions developed previously, providing intermediate 2.74 in 68% yield (Scheme 2- 17). Dithiane removal was similarly successful with the optimal conditions from the first route. With the resulting product 2.75 readily available, simultaneous reduction of the hydroxy ketone
and differentiation of the resulting diol was required. The Evans-Tischenko reduction25 with
benzaldehyde was chosen to fulfill these goals. This strategy would permit the formation of a benzoate at C(13), a group that could be removed orthogonally with respect to both the C(21) PMB ether and the C(22) TES ether after union with 2.72 (Scheme 2-20).
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After considerable optimization, we found that the reduction of 2.75 was best conducted via the portionwise addition of a freshly prepared samarium diiodide solution over the course of 8
hours in the presence of 15 equivalents of freshly distilled benzaldehyde, providing the desired anti-diol 2.76 in 84% yield as a single observable isomer. We were surprised to observe the
formation of a second product, initially suspected to be the C(11) diastereomer. However, after careful separation and extensive NMR structural investigation, the byproduct was identified as 2.78 after TBS protection to assist purification. This byproduct has its origins in the initial ARC step where, at higher temperatures, excess TBS-dithiane can attack two equivalents of the excess epoxide 2.29 to form semi-symmetrical adduct 2.77, which is inseparable both at this stage and after dithiane removal.
Identification of 2.77 as a byproduct of the ARC step led us to reconsider the conditions for the ARC union in both the inverted and regular order of addition (vide supra). We reasoned that the symmetrical adduct was arising after introduction of epoxide 2.29 (Scheme 2-18). That is, immediately after Brook rearrangement the anion 2.42-Li is present in significantly larger quantities and should react with epoxide 2.29 significantly faster. We therefore reasoned that by lowering the temperature of the second epoxide addition, the rate of product formation would not be significantly influenced, while the rate of formation of byproduct 2.77 would decrease sufficiently such that double addition would not take place.
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Indeed, when the second epoxide addition was maintained below 0 °C, the ARC product was isolated as a single compound in a similar yield as before. Importantly, when this chromatographically pure compound was carried through to the Evans-Tischenko reduction, a single diastereomer was obtained in 84% yield. The remaining hydroxyl was next protected as the TBS ether to yield 2.79 (Scheme 2-19). Removal of the primary benzyl group and careful
oxidation with Dess-Martin periodinane (DMP)26 then provided aldehyde fragment 2.72. Two
details are of note. First, oxidation to the aldehyde proved highly sensitive, as conditions other
than DMP resulted in exclusive elimination of the benzoate to form the corresponding α,β-
unsaturated congener, a fact that foreshadowed future difficulties (vide infra). Second, the decision to move away from TES protection at C(13) was highly beneficial in terms of yield - whereas in our previous sequence (see Scheme 2-9) yields were generally low due to partial loss of the labile C(13) TES ether, the late stage manipulations in Scheme 2-17 proceeded in uniformly high yield.
Scheme 2-19 Completion of aldehyde 2.72
Aldehyde 2.72 available from the above sequence was next coupled with the previously constructed alkyne 2.26, again utilizing a non-selective alkynylation protocol (Scheme 2-20). The diastereomers were readily separated by standard column chromatography and each isomer subjected to a two stage deprotection sequence, involving DIBAL-H mediated removal of the benzoyl group, following by oxidative removal of the PMB group. On small scale, this sequence readily provided samples of spiroketalization precursors syn-2.80 and anti-2.80. Note that the syn and anti designations are assigned here to match the syn and anti designations in the Aponick and Forsyth cases described in Scheme 2-13.
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Scheme 2-20 Synthesis of two spiroketalization precursors
With the appropriate precursors in hand, we moved on to the critical gold catalyzed spiroketalization step (Scheme 2-21). Pleasingly, when anti-2.81 was treated with cationic
JohnPhos ligated gold complex 2.82,27 a new product was isolated in 81% yield, which, after
extensive 1D and 2D NMR analysis, proved to be the desired spiroketal 2.15.
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The stereochemistry of the spiroketal core was confirmed by observation of a key nOe between the C(13) and C(21) protons (Figure 2-2); a similar nOe was observed by Patterson in a
related system.28
Figure 2-4 Key observed nOe confirming spiroketal stereochemistry
Conversely, when syn-2.81 (Scheme 2-21) was subjected to the same spiroketalization conditions, none of the desired spiroketal was identified. Unfortunately, poor purity and instability to silica gel precluded the full structural characterization of this compound, though based on results that will be described in Chapter 3, we can now assign the structure to be 2.83 (Scheme 2-21).
In conclusion, the first synthesis of the proposed southern hemisphere fragment for spirastrellolide E, namely C(1)-C(24) spiroketal 2.15, has been achieved, proceeding in 19 steps (longest linear sequence) and a 2% overall yield. An account of the synthesis of 2.15 was published in a 2015 Tetrahedron Letters Special Issue to honor and remember Henry
Wasserman, Yale University (1948-2013).29
Figure 2-5 Southern hemisphere 2.15