Dr Florine Cavelier
Directeur de Recherche CNRS
IBMM – UMR 5247
Université Montpellier 2 – CC 1703
Phone 33 (0)467 14 3 844 - Fax 33 (0)467 144 866
florine.cavelier@univ-montp2.fr
Dear Jeffrey Bode,
We are pleased to send you the article entitled " (L)-(Trimethylsilyl)alanine
synthesis exploiting hydroxypinanone-induced diastereoselective alkylation”.
This article is the revised form of a previously sent manuscript, referenced AMAC-D13-00055 and initially entitled « (L)-(Trimethylsilyl)alanine synthesis is more selective
with an electronegative chiral imine ».
We submitted a revised version of the manuscript in which the changes are
highlighted in yellow and below, we have explained point-by-point how we have addressed
the comments raised by each Reviewer. Some of the comments requested complementary
experiments, which have been accomplished: recovery of chiral inductor, and extension of
the method. These new results have been added in the revised version.
We hope that this revised version of the manuscript will be considered for publication
in Amino Acids.
Sincerely yours,
Florine Cavelier
Response to Reviewers
Reviewer #1: The authors have described a practical and efficient protocol for the
preparation of enantio-enriched (L)-(Trimethylsilyl)alanine based on chiral auxiliary-induced
diastereoselective alkylation. Although there are several reported procedures for this
compound, the present method is a nice alterative due to step-economy and efficiency. This
paper can be accepted after major revision on the basis of the following comments being
taken into consideration.
1. Since the chiral auxiliary-based methodology is neither catalytic or atom economical,
it is still practical if the auxiliary can be recovered and reused without racemization. In
this manuscript, the expensive chiral auxiliary was removed under acidic condition.
Could this auxiliary be recovered without decomposition and racemization? If could,
please provide the detailed procedure in experimental section.
We tried to recover the chiral inductor by ether extraction as explained in the work up in
experimental part. However, the recovered hydroxypinanone was epimerised as proved by an
[α]D20 value around +5 (against +39 initially) and by the NMR analysis, which displayed a
splitting signal for the hydrogen vicinal to the hydroxyle.
Therefore, we did not mention this result neither show the NMR spectra but this can be
added in the supporting information if the reviewer finds it necessary.
2. Could this method extend to other silylated amino acids? It is good plus if two more
examples, such as TES-, TBS-alanine, are provided.
We performed the alkylation of the hydroxypinanone Schiff base with two other silylated
reagents, thus providing two amino acids with (CH2)3SiMe3 and CH2SiMe2Ph as side chain
respectively.
These results have been added in the manuscript, Scheme 4 and compounds 13 and 14 have
been described in experimental part (1.6 and 1.7).
3. The key alkylation step is diastereoselective. So the de or dr value of compound 11
should be given.
The diastereoselectivity was beyond the precision of the NMR technique (see spectra of 11
in supporting information). A sentence has been added to give this point in the manuscript in
the text under the Scheme 2.
4. The ee value of final Fmoc-protected amino acid is 98%. It is not enough for SPPS.
Could the optical purity be further increased by recrystallization of compound 11 or
Fmoc-protected amino acid.
We did not attempt any recrystallization to improve optical purity.
Reviewer #2: Manuscript AMAC-D-13-00055
Entitled: (L)-(Trimethylsilyl)alanine is more selective with an electronegative chiral imine
A. René, N. Vanthuyne, J. Martinez, F. Cavelier
This manuscript describes a comparative study for the stereoselective synthesis of (L)(trimethylsilyl)alanine according three strategies, using chiral inductors such as S-chiral
sulfinimides or hydroxypinanone. In the case of the (S)-(+)-p-tolylsulfinamide, the reaction
of the Schiff base derived from methyl glyoxylate with a silyl Grignard reagent, afford a
mixture of epimers in low yields. When the (S)-t-butyl sulfinamide was used, the
trimethylsilyl organometallic reagent do not react with the corresponding Shiff base. On the
other hand, in the case of the Shiff base derived from hydroxypinanone, the reaction of the
derived enolate is highly diastereoselective and the desired product is obtained with 58%
yield in a five steps synthesis.
The stereoselective synthesis of (trimethylsilyl)alanine has been already described, but
generally the methods are based on enzymatic resolutions. In continuation of their work on
the synthesis of silyl aminoacid derivatives, and their preliminary results in Chem &
Biodiversity (2008), the authors clearly reported here the feature that a better stereoselective
synthesis of Fmoc-(trimethylsilyl)alanine useful for SPPS, was obtained using the alkylation
of the Shiff base derived from hydroxypinanone.
The bibliography is particularly well exemplified and useful for the chemist interested in the
silyl-aminoacids derivatives.
The manuscript could be accepted for publication after corrections:
- The title is uncleared and must be changed
As suggested, we propose an other title: « (L)-(Trimethylsilyl)alanine synthesis
exploiting hydroxypinanone-induced diastereoselective alkylation ».
- The quality of the Schemes and specially Scheme 1, is very poor
- Compounds 2, 3, 11, 12: the 13C NMR spectra must be described in the experimental part;
All requested 13C NMR have been added.
- In the supporting information for the 13C NMR spectra correct frequency (75 Hz not 300,
150 Hz not 600 for compounds 2, 3, 5, 11, 12)
page 2, line 14 ( 1R,2R, 5R) ) R in italic
page 2: line 54… Bruker spectrometer Avance (not Advance) several times.
page 3: line 16 (S)- in italic
page 3: line 19 MgSO4
page 3: lines 23, 24 J in italic
page 3: line 45: 1H NMR of 3, to correct the chemical shift of the quadruplet
page 4: line18: 1.30 (s….
page 4: line 54: … in term of chimio- and stereoselectivities
page 5: line 18: t-butyl sulfinamide auxiliary
page 5: line 21: t-butyl sulfinamide 6:
page 5 line 46: boron trifluoride diethyl ether
page 6 line 16 [α]
page 6 line45- 46 On the other hand, the Shift base derived from hydroxyl pinanone
was used as equivalent nucleophile of the glycine.
page 6, line 47 diastereoselective
page 7 line 18: Böhm (2009)
page 7, line 17, 22, 31, 47 delete the Doi
page 7 line 21 (2009)
page 7 line 57, 58 (2000)
page 8 line1 DE patent 3841319 (1989)
We thank the reviewer for his remarks and we made all the detailed corrections.
Reviewer #3: The manuscript by Cavelier describes the synthesis of L(trimethylsilyl)alanine via alkylation of a chiral Schiff base. The new synthetic approach
towards the silylated amino acid is interesting. However, the manuscript is not really well
written and needs carful revision by the authors. Nevertheless, acceptance of the manuscript
after appropriate alterations is recommended.
1) The title of the manuscript is confusing and does not make sense. First of all, its not
TMSAla which is more selective, but the synthesis towards it (or better said the chiral
auxiliary). Second, the name of the used chiral auxiliary should be in the title.
As already mentioned, a new title has been proposed.
2) There are several typos or unclear formulations in the manuscript (e.g. p2, line20
"silicon affected chemical properties of compounds..." not "afford physical and
chemical properties"; p2, line 40, "on a gram scale" not "at the gram scale"; several
times "the TMSAla", the "the" is not necessary; page4 line55 "alkylation reaction
permitted to evaluate the chiral induction control of each method" What does that
mean?; p4, line57 "sulfoxyde group" is wrong, ether "sulfoxide" or "sulfonamide";
page 6, line 44 "on the one hand" not "in one hand" etc.).
We do not agree with the first modification, which changes the meaning of the sentence.
The word « afford » is appropriate, but can be replaced with « confer » if preferred. However
“affect” suggested by the Reviewer has not the same signification.
The sentence page 4 line 55 «alkylation reaction permitted to evaluate the chiral induction
control of each method » has been replaced by « alkylation reaction permitted to evaluate the
chiral induction of each auxiliary ». Others corrections were done.
3) The "materials and method" part has several wrong expressions and inconsistencies
and should be carefully revised by the authors (e.g. "heating was continued for 10
minutes" not "heating was kept on 10 minutes more", "the desired diastereomer" not
"the wanted diastereoisomer"; "potassium carbonate" not "carbonate potassium"; one
time "magnesium sulphate" but otherwise always "MgSO4"; one time BF3OEt2 then
trifluoroboride etherate; one time "concentrated in vacuo" or "removed in vacuo" but
otherwise always "concentrated"; the significant digits during an experimental
procedure should be consistent through out the document)
All corrections have been integrated to improve the quality of the text, including the
experimental part.
4) A new review on organosilicon compounds in medicinal chemistry appeared this year
and should be cited (Franz. J. Med. Chem. 2013, 56, 388-405).
This reference has been added as drug design support, in the introduction.
5) Chemical suggestions: Concerning the addition to the tert-butyl sulfiniminoacetate:
Did the authors try to use a bulkier ester group in order to avoid attack of the Grignard
at the ester functionality (e.g. tert-butyl ester)? Was the addition to the sulfonamide
ever carried out with an organocopper reagent? Organocopper reagents are more
reactive than organozinc reagents and a better conversion at -78 ºC could be observed.
The commercially starting material for the synthesis of the sulfinimine derivative is
available in ethyl ester only (ethyl glyoxalate).
Organocopper is an interesting suggestion but we did not try since the other pathway using
hydroxypinanone was successful in the mean time.