Harvesting short-lived hypoiodous acid for efficient diastereoselective iodohydroxylation in Crixivan synthesis

Article abstract of DOI:10.1016/S0040-4039(01)01863-9

The evasive hypoiodous acid is generated in situ from NaOCl and NaI and used efficiently for clean iodohydroxylation of 1, producing the Crixivan intermediate 2 in high yield with highly efficient 1,3-asymmetric induction. This pH-tunable process allows H

Full text of DOI:10.1016/S0040-4039(01)01863-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8603–8606
Harvesting short-lived hypoiodous acid for efficient
diastereoselective iodohydroxylation in Crixivan® synthesis
Carl R. LeBlond, Kai Rossen, Frank P. Gortsema, Ilia A. Zavialov, Steven J. Cianciosi,
Arthur T. Andrews and Yongkui Sun*
Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 12 September 2001; revised 26 September 2001; accepted 4 October 2001
Abstract—The evasive hypoiodous acid is generated in situ from NaOCl and NaI and used efficiently for clean iodohydroxylation
of 1, producing the Crixivan® intermediate 2 in high yield with highly efficient 1,3-asymmetric induction. This pH-tunable process
allows HOI generation at a pH optimal for supressing byproduct formation in pH-sensitive iodohydroxylation reactions. © 2001
Published by Elsevier Science Ltd.
Diasteroeselective iodohydroxylation of 2-alkyl-4-
enamide 1 to iodohydrin 2 is a key step in the synthesis
of Merck’s HIV protease inhibitor Crixivan® (indinavir
sulfate). The iodohydrin is converted to the correspond-
ing epoxide and further elaborated to indinavir
(Scheme 1).1 The iodohydroxylation step has been
accomplished with high diastereoselectivity and high
yield using N-iodosuccinimide (NIS) or N-chlorosuc-
cinimide (NCS) with sodium iodide in a buffered bipha-
sic reaction system [isopropyl acetate (IPAc)/aq.
NaHCO3].1a Pathway of the reaction is pH sensitive.
The amide bond cleavage reaction leading to byproduct
3 increases significantly with decreasing pH. Thus, it is
desirable to conduct the reaction at high pH to mini-
mize byproduct formation. However, NIS becomes
increasingly unstable with increasing pH above 8.
tive hydrolysis in the presence of HgO, converts 1 to 2
with high stereoselectivity and good yield.2 It would be
of great interest to develop a practical and pH-tunable
method that produces active hypoiodous acid cleanly
and efficiently over a wide range of pHs, and in this
case, at high pH optimal for the iodohydroxylation
reaction.
Few methods of producing HOI are currently available
and they either require strongly acidic conditions,3 or
utilize molecular iodine (which is either used as starting
material4 or generated in situ via oxidation of NaI5).
Other efforts include reduction of periodic acid or
sodium periodate by sodium bisulfite,6 and oxidation of
iodomethane by dimethyldioxirane.7 Acidic conditions
are incompatible with substrate 1, while the use of
iodine leads to numerous impurities including lactones
3 and oxazoline 4.8 We describe here a novel and
practical chemical process wherein HOI is generated in
It has been reported that hypoiodous acid (HOI), gen-
erated electrochemically or via iodine disproportiona-
N
OH
OH
"I+"
N
O
I
OH
NH
N
O
O
N
N
O
O
O
t-Bu
N
H
Indinavir
1
2
.
Scheme 1.
* Corresponding author. Tel.: +1-732-594-1643; fax: +1-732-594-9210; e-mail: yongkui sun@merck.com
–
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01863-9

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C. R. LeBlond et al. / Tetrahedron Letters 42 (2001) 8603–8606
1/IPAc/aq. NaHCO3 biphase in order to avoid an
excess of either NaOCl or NaI and thus minimize the
unproductive HOI degradation. Since the rate of reac-
tion with 1 is most likely first order in [HOI], while the
rate of HOI disproportionation is second order in
[HOI],12 the concurrent addition of NaOCl and NaI
should be sufficiently slow to favor iodohydroxylation
over HOI disproportionation.
situ from readily available NaOCl and NaI at a pH
optimal for selectivity and captured efficiently to con-
vert 1 to iodohydrin 2 in excellent yield (96%) with
highly efficient 1,3-asymmetric induction (96% de).
Due to its reactive nature, hypoiodous acid can not be
prepared using conventional methods,9 and its charac-
terization has been challenging.10 Reaction of NaOCl
with NaI in aqueous phase produces hypoiodous acid,
or hypoiodite depending on pH. Using this reaction,
Chia and Lister produced HOI, measured its formation
kinetics, and recorded its electronic spectrum.11
We found that the best iodohydroxylation results are
achieved when the NaOCl (2 equiv.) and NaI (1.8
equiv.) solutions were fed concurrently but separately
to the agitated 1/IPAc/aq. NaHCO3 biphase over 1 h,
with the reaction pH controlled in the 8–9.5 range by
on-demand addition of dilute sulfuric acid.13 Under
these reaction conditions, the iodohydroxylation of 1
was nearly complete (99.9% conversion) to give 2 in
96% de and 96% yield13 at the end of 1 h addition of
NaOCl and NaI (Fig. 1). The success of this simple
NaOCl/NaI process demonstrates that highly reactive
HOI generated in situ was sufficiently long-lived under
these reaction conditions to convert cleanly 1 to iodo-
hydrin 2. The success also indicates that the reaction
between HOI and 1 is much faster than HOI dispropor-
tionation. Fig. 1 shows that the rate of iodohydroxyla-
tion was so fast that it was limited by the addition rate.
Ph
OH
Ph
O
I
R
R = H, I
I
N
O
O
4
3
.
We attempted to use this simple reaction to generate
HOI in situ for iodohydroxylation of 1. Due to the
highly unstable nature of HOI under normal condi-
tions, its clean chemical generation is challenging.
Scheme 2 describes a few key pathways for HOI forma-
tion from NaOCl/NaI and its degradation. Since the
reaction between NaOCl and NaI is extremely fast and
exceeds the rate of HOI disproportionation,11,12 we
expect that it is possible to build up HOI in solution in
significant concentrations for iodohydroxylation. How-
ever, in addition to the desired iodohydroxylation and
the undesired disproportionation, HOI can also be
oxidized by excess NaOCl to inactive species such as
iodate, or react with excess NaI to give iodine. This
implies that the outcome of using NaOCl/NaI to gener-
ate HOI for iodohydroxylation depends on the mode
and ratio of NaOCl/NaI addition.
Several other characteristics of this process are dis-
cussed below. Firstly, the reaction pH is a critical
reaction parameter as can be seen from Fig. 2 where the
conversion of 1 at the end of reagent addition is plotted
Addition of NaOCl to the reaction already containing
NaI would result in reduction of HOI to iodine that is
known to react with 1 to give numerous byproducts.8
Alternatively, addition of NaI to the batch charged
with NaOCl would lead to oxidation of HOI (pre-
sumably to iodate) and thus no substrate conversion. A
successful experimental protocol for generating HOI in
solution should employ concurrent but separate addition
of NaOCl and NaI in nearly equal molar ratio to the
Figure 1. Conversion of 1 to 2 as a function of time during
co-addition of NaOCl and NaI (dash line is the addition
profile).
.
Iodohydrin 2
(1) 1
-
(2) OCl-
IO3
HOCl + I-
HOI
(3) l-
OCl-
(5)
2HOI
I2
(4)
IO3- + I-
.
Scheme 2. Fate of HOI.

C. R. LeBlond et al. / Tetrahedron Letters 42 (2001) 8603–8606
8605
expected, the addition of NaI to a mixture of NaOCl/1/
IPAc/aq. NaHCO3 in the pH range 9–12 gave no
desired product. When NaOCl was added to the mix-
ture NaI/1/IPAc/aq. NaHCO3 at pH 8.0–9.5, poor
conversion (11%) and a high level of impurity 4 were
observed during the addition of the first half of the
NaOCl solution. However, greater than 99% conver-
sion was achieved upon addition of the second half of
NaOCl. These observations were consistent with the
proposed reaction pathways whereby during addition
of the first half of NaOCl solution, HOI generated can
not react with 1 due to its fast reaction with the excess
iodide to I2. During the second half of NaOCl addition,
NaI is depleted and I2 is oxidized by NaOCl to give two
moles of HOI (step 5 in Scheme 2).16
Figure 2. Effect of reaction pH on the conversion (solid
circle) of iodohydroxylation of 1 to 2, and its correlation to
HOI% (HOI%=[HOI]/([HOI]+[OI−], dashed line) as a func-
tion of pH.
Finally, the greater than 50% conversion at midpoint of
NaOCl/NaI addition in Fig. 1 implies that the iodide
usage (1.8 equiv.) may be reduced. Indeed, the use of
1.4 equiv. of iodide (with 1.6 equiv. NaOCl) is sufficient
to reach complete conversion.
versus the reaction pH. The fact that the conversion
falls precipitously with pH>9.5 may result from two
factors. One is related to the fact that the rate of
formation of hypoiodous acid from NaOCl and NaI is
inversely proportional to [OH−].11b,14 The slower HOI
formation rate results in enhanced degradation of HOI
by reacting with the unreacted NaOCl and NaI. Fur-
thermore, HOI, instead of OI−, is likely the principal
iodination species in this biphasic system, and extrac-
tion of HOI into the organic phase is a key step. The
latter is supported by the apparent correlation between
conversion and the HOI percentage shown in Fig. 2.
Since HOI is a weak acid (pKa=10.7),9 at pH below
9.5, >95% of the I+1 species exists in the form of HOI
which is extracted into organic phase where it is shel-
tered from degradation reactions with NaOCl and NaI
in the aqueous phase. The conversion is high as a
result. At high pHs, e.g. pH=12.5, the I+1 species exists
predominantly as hypoiodite that resides in the aqueous
phase, unable to react with 1 and eventually destroyed.
In summary, we have developed a new, efficient, and
pH-tunable iodohydroxylation method. This method
has been demonstrated for preparation of Crixivan®
iodohydrin 2 in high yield with highly efficient 1,3-
asymmetric induction. The key to the success of this
chemistry is a carefully designed experimental protocol
that minimizes side reactions and allows for clean in
situ generation of reactive iodination species,
hypoiodous acid, at a pH optimal for selectivity.
Among the advantages of this new process are its high
operating pH and minimization of iodine formation
that suppress formation of byproducts, inexpensive and
nontoxic reagents, fast reaction rate, simple product
isolation procedure, high iodine utilization efficiency,
and elimination of organics (e.g. succinimide) in the
waste stream. Studies of this chemistry as a general
synthetic utility for iodination are in progress.
Secondly, yield of iodohydroxylation of 1 to 2 using
NaOCl/NaI (96%) is higher than typical yield of the
NCS/NaI process (90–92%) primarily due to reduced
levels of byproducts 3 and 4. The pH-tunable nature of
the NaOCl/NaI process allows the HOI generation at a
reaction pH optimal for selectivity. Since low pHs favor
amide bond cleavage and formation of 3,1,15 the ability
of the NaOCl/NaI process to operate at high reaction
pH (up to 9.5) strongly suppressed the amide bond
cleavage pathway. The level of 3 is reduced by a factor
of four compared with the NCS/NaI process (pH=7.2–
8.0). Since the commonly employed NCS and NIS are
unstable at pH>8.5, the new NaOCl/NaI process
should prove more beneficial in iodohydroxylation of
2-alkyl-4-enamides in general. The decrease in the
amount of impurity 4 can be rationalized by the fact
that in our controlled NaOCl/NaI process HOI is gen-
erated more cleanly with minimal degradation to iodine
which is the principal cause behind the formation of
impurity 4.
Acknowledgements
We thank Dr. Charles J. Orella for helpful discussion
and Dr. Shane W. Krska for critical comments on the
manuscript.
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