Scheme 2
ous pyridine7,10 led to a diastereoselective formation of the
about concurrent hydrogenolysis of the aminoacetal func-
tionality, 14 was first converted into the secondary amine
14 (Cbz ) H), [R]24D -120.7 (c 0.4, CHCl3), under standard
palladium-mediated hydrogenolysis conditions, which then
was treated with formalin in the presence of sodium
single carbinolamine 7, [R]25D -104.1 (c 0.7, CHCl3), in 70%
yield without affecting the siloxy protecting group. On
reduction with lithium aluminum hydride followed by
alkaline workup in the presence of carbobenzoxy chloride,
7 furnished the indoline N-carbamate 8, [R]26D +1.5 (c 1.2,
CHCl3), as a single diastereomer. The overall yield of 8 from
(-)-1 was 45% in four steps. Although the stereochemistry
of 8 could not be determined at this stage, the key Fischer
indolization sequence involving a [3.3]-sigmatropic re-
arrangement was confirmed to proceed diastereoselectively
from the convex-face through diaza-1,5-diene intermediate
6 by acquisition of the known tricyclic aminoacetal7 (-)-15
at a later stage (Scheme 2).
cyanoborohydride to give 15, [R]28 -94.9 (c 0.4, CHCl3)
D
[lit.7 [R]32 -96 (c 0.35, CHCl3)]. At this point it was
D
confirmed that the key Fischer indolization had occurred
diastereoselectively from the convex-face of the intermediate
6 as anticipated. The overall yield of the N-methylamino-
acetal (-)-15 from 12 was 43% in four steps. Since the
aminoacetal (-)-15 has been transformed into (-)-physo-
venine (2) in two steps,7 the present acquisition of (-)-15
constitutes a formal synthesis of the alkaloid (Scheme 3).
Employing the same technology as that developed in the
sugar synthesis,1,2 the acetal functionality in 8 was next
cleaved in a sequence of four reactions. Thus, alcohol 9,
[R]26D +22.9 (c 1.0, CHCl3), obtained from 8 by desilylation,
was transformed sequentially, under standard conditions, into
Scheme 3
mesylate 10, [R]26 +12.7 (c 1.1,CHCl3), and iodide 11,
D
[R]25 -45.8 (c 1.0, CHCl3), which was exposed to zinc in
D
hot ethanol containing acetic acid to initiate reductive
cleavage of the internal acetal linkage to give rise to vinyl-
hemiacetal 12 as an epimeric mixture. The overall yield of
12 from 8 was 86%. The mixture 12 was used as the common
intermediate for both (-)-physovenine (2) and (-)-physo-
stigmine (3).
To obtain (-)-physovenine (2), 12 was first reduced with
sodium borohydride to give the diol 13, [R]30D +28.5 (c 0.4,
CHCl3). After extensive examination, it was found that the
removal of an extra three-carbon moiety from 13 was best
carried out in one step with lead(IV) acetate.11 Thus, on
exposure to 3 equiv of lead(IV) acetate in benzene at room
temperature, 13 afforded tricyclic carbamate 14, [R]24D -45.2
(c 0.4, CHCl3), in 53% yield by concurrent oxidative removal
of the three-carbon allylic alcohol moiety and cyclization.
Since an attempted one-step conversion of 14 into the known
tricyclic N-methyl aminoacetal7 15 under catalytic hydro-
genolysis conditions in the presence of formalin12 brought
To obtain (-)-physostigmine (3), 12 was first heated with
methylamine hydrochloride in methanol in a sealed tube in
the presence of sodium cyanoborohydride at 90 °C for 12 h
to afford the N-methylaminoalcohol 16, [R]26D +10.5 (c 0.5,
CHCl3), which was converted into the bis-carbamate 17,
(10) Welch, W. M. Synthesis 1977, 645.
(11) Suginome, H.; Umeda, H.; Masamune, T. Tetrahedron Lett. 1970,
4571.
(12) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R. Org.
Lett. 1999, 1, 229.
2758
Org. Lett., Vol. 2, No. 18, 2000