II. RAPID GENERAL ACCESS TO AZABICYCLIC RINGS SYSTEMS AND
2.9 Progress Towards Stemaphylline Via Indium-Mediated Allylation
resulting allylic alcohol was subjected to Sharpless epoxidation conditions. The desired epoxide was cleanly formed in 95% yield. Unfortunately, attempts at the Appel reaction and subsequent elimination/ring-opening of the epoxide resulted in complex mixtures of products (Scheme 2.8.7).
Scheme 2.8.7 Failed completion of stemaphylline via chiral sulfinamides.
With poor selectivity in the Grignard addition and no reaction in the subsequent epoxidation, we decided to explore a new route to the natural product.
Scheme 2.9.1 Indium-mediated allylation.
Based on this work, we designed a route to stemaphylline making use of a complex allylic bromide to install the stereochemistry at C-9 and C-9a. Outlined in Scheme 2.9.2 is our new retrosynthetic analysis of stemaphylline.
Scheme 2.9.2 Retrosynthetic analysis of stemaphylline via indium-mediated allylation.
To test the viability of the above strategy, a model azabicyclic skeleton was prepared in excellent enantiopurity starting from 6-chloro-1-hexanal (Scheme 2.9.3).
Ph H
N S
O Br
In (4.0 eq) sat aq NaBr, rt, 12 h
Ph HN S
O
H N S
O Br
In (4.0 eq) sat aq NaBr, rt, 12 h
HN S O Ph
F
Ph F
2.127 2.128
2.129 2.130
Scheme 2.9.3 Rapid, general synthesis of azabicyclic ring systems
The chloroalkyl N-(tert-butanesulfinyl)aldimine was easily prepared in 94% yield by condensing the corresponding chloroaldehyde with the Ellman (S)-tert- butanesulfinamide. A subsequent indium-mediated allylation reaction afforded the anticipated product in >9:1 diastereoselectivity and 86% yield. Acid-mediated liberation of the primary amine followed by base-induced, microwave-assisted cyclization and alkylation with allyl bromide smoothly afforded the chiral N-alkyl azepane in 65% yield for the three-step, one-pot reaction sequence. A survey of the literature regarding RCM methods with tertiary amines suggested that protection of the amine by in situ generation of ammonium salts enabled facile ring-closing.41 Thus, treatment of diene 2.137 with trifluoroacetic acid (TFA) in toluene, followed by the addition of Grubbs II and microwave heating for 1 hour at 100 oC, provided the unsaturated pyrido[1,2-α]azepine ring system in 68% isolated yield and 35% overall yield from commercially available starting materials.
Previous efforts in our lab towards the enantioselective synthesis of azabicyclic
significant drawbacks, including the need for different transformations depending on the desired ring size, inconsistencies in alkylation of the tert-butanesulfinyl nitrogen, and the lack of ability to access multiple rings from a single lynchpin intermediate. Encouraged by the results of our model system, we opted to develop this into a general methodology that would allow rapid access to diverse small to large azabicyclic ring systems (Scheme 2.9.4).
Scheme 2.9.4 Envisioned route to access diverse 1-azabicyclo[m.n.0]alkane cores.
Following the same method described above for the model system, the chloroalkyl N-(tert-butanesulfinyl)aldimines were easily prepared in 92-94% yields by condensing the corresponding chloroaldehydes with the Ellman (S)-tert- butanesulfinamide. A subsequent indium-mediated allylation reaction afforded the anticipated (R)-anti-adducts in >9:1 diastereoselectivity and 85-86% yield. Acid- mediated deprotection and base-induced, microwave-assisted cyclization and alkylation with the required allyl, butenyl and pentenyl bromides smoothly afforded the chiral N- alkyl ring systems in 63-83% yields for the three-step, one-pot reaction sequence
Scheme 2.9.5 Enantioselective synthesis of N-alkyl rings.
Yields for the RCM reaction averaged 70% for all the substrates, providing high-yielding, enantioselective access to each of the 1-azabicyclo[m.n.0]alkane systems. Overall yields from the commercial chloroaldehydes ranged from 29-59%. This work provides a general route to access these important azabicyclic ring systems with an embedded olefin handle for further functionalization (Figure 2.9.1).42
Figure 2.9.1 Mono-unsaturated 1-azabicyclo[m.n.0]alkane ring systems.
Once the conditions for the methodology were optimized, we moved on to its application in the total synthesis of stemaphylline. The required chloroalkyl N-(tert- butanesulfinyl)aldimine was easily prepared from the corresponding alcohol in 93% yield (Scheme 2.9.5). We then shifted our focus towards the synthesis of the required complex allylic bromide for the indium-mediated allylation.
The synthesis of the allylic bromide emanated from a Myers alkylation of (1R,2R)-(−)-pseudoephedrinepropionamide with TBDPS protected iodoethanol which proceeded in 83% yield. Reductive cleavage of the chiral auxiliary and subsequent Ley oxidation to the corresponding aldehyde gave the chiral, α-methyl aldehyde in 65% yield over two steps. The aldehyde was subjected to a Horner-Wadsworth-Emmons olefination with triethyl phosphonoacetate to give the α,β-unsaturated ester in 81% yield. Reduction of the ester to the allylic alcohol with diisobutylaluminum hydride (DIBAL) followed by an Appel reaction afforded the allylic bromide in 89% yield over two steps (Scheme
Scheme 2.9.6 Synthesis of allylic bromide.
With the allylic bromide in hand we attempted the indium-mediated allylation on the chloroalkyl imine. Regrettably, the allylation resulted in only starting material after stirring for 3 days at room temperature, and only about 5% conversion to product by LCMS after heating for an additional 3 days with no isolatable product (Scheme 2.9.8).
Scheme 2.9.7 Attempted indium-mediated allylation in route to stemaphylline.
Based on these results, we decided to perform a screen of allylic bromides to test the limits of the indium-mediated allylation. Using crotyl bromide, we found that the
indium-mediated allylation smoothly provided the allylated product in 91% yield. When 1-bromo-4-methylpent-2-ene was used, the allylated product was obtained in only 6%
isolated yield. This indicated that when branching is introduced into the allylic bromide at the 4-position the reactivity is greatly reduced (Scheme 2.9.9). Based on these results we chose to explore a new way to intercept the same intermediates from the indium route.
Scheme 2.9.8 Effect of olefin substitution on indium-mediated allylation.