to quantitatively study the product distribution
over time using^1 Hand^19 Fnuclearmagnetic
resonance (NMR) spectroscopic techniques.
The medium was homogeneous early in the
reaction, and no significant preference for
any product diastereomer was observed. A
mixture of four diastereomers was initially
present in solution. The onset of crystalliza-
tion (t ~ 3 hours) initiated product diastereo-
mer enrichment through CIDT at the expense
of the three more soluble, equilibrating dia-
stereomers. Reaction progress was marked
by steady perturbation of the isomer ratio
away from the unselective solution equilib-rium (t = 1 hour), continuingover the course of
the 48-hour reaction to result in the highly
enriched product.
Epimerization through retro-Michael reversion/
Michael addition ( 20 )wasinvestigatedthrough
a crossover experiment. Upon exposure of nitro-
ethane adduct4b to the action of iminophos-
phoraneAin the presence of excess nitromethane
(20 equiv) under homogeneous reaction con-
ditions for 48 hours, none of the crossover
product3b was identified; rather, epimerized
4b and other unidentified decomposition
products were observed (Fig. 4C). This ex-
periment underscored an important corollary:
Crystallization insulates the product from un-
desired decomposition pathways that occur
in the homogeneous environment commonly
favored for organic reactions.
With a mechanistic understanding in hand to
rationalize the excellent stereocontrol observed
in this reaction platform, an assessment of some
of the practical features of the doubly stereo-
convergent crystallization was undertaken
(Fig. 5). A reaction using 25 g of alkylidene 2
was performed with excess nitroethane. A
lower-molecular-weight iminophosphorane (B)
was used, which efficiently catalyzed the desired
CIDT reaction to deliver nitroalkane4i in good
yield and stereoselectivity after a single filtra-
tion. When the unpurified homogeneous filtrate
containing catalyst and residual excess nitro-
ethane was treated with another 25 g charge
of prochiral alkylidene 2 , nitroalkane4i was
obtained with nearly identical efficiency in
the second cycle. The product was enriched to
enantiomeric homogeneity with good recoveryde Jesús Cruzet al., Science 376 , 1224–1230 (2022) 10 June 2022 6of7
Fig. 5. Synthetic utility of the crystallization-
enabled doubly stereoconvergent conjugate addi-
tion.See the supplementary materials for specific
reaction details. (A) A 50 g doubly stereoconvergent
crystallization enabled by catalyst recycling. Reaction
conditions were as follows: (i) cat.B (20 mol %),
alkylidene 2 (80.3 mmol, 1.0 equiv), EtNO 2 (241.0 mmol,
3.0 equiv), 2-Me-THF (80 ml, 1.0 M), 23°C, 48 hours.
(ii) Unpurified homogeneous filtrate containing
catalyst and excess nitroalkane was charged with
(80.3 mmol, 1.0 equiv) of prochiral alkylidene 2.
(iii ) Recrystallization from 80% EtOAc:hexanes.
(B) Diastereoselective synthesis of secondary
and tertiary alcohols. (iv to viii)nitroalkane 4i
(0.100 mmol, 1.0 equiv), CeCl 3 (0.300 mmol, 3.0 equiv),
LiCl (0.600 mmol, 6.0 equiv), RMgX (0.180 mmol,
1.8 equiv) THF/DCM (5:1),–78°C, 12 hours. (ix)nitro-
alkane4i (0.100 mmol, 1.0 equiv), TiCl 4 (0.110 mmol,
1.1 equiv), BH 3 • DMS (0.500 mmol, 5.0 equiv), DCM,- 78°C, 5 hours. (C) Reductive cyclization and synthetic
utility of the amide functional handle. (x)nitroalkane
4i (1.5 mmol, 1.0 equiv), Zn (45.0 mmol, 30 equiv),
AcOH,65°C,5hours.(xi)nitroalkane4i (0.200 mmol,
1.0 equiv), LiAlH 4 (0.800 mmol, 4.0 equiv), THF,
23°C, 2 hours.
RESEARCH | REPORT