A novel regio- and stereoselective synthesis of sulfamidates from 1,2-diols using Burgess and related reagents: A facile entry into β-amino alcohols

Article abstract of DOI:10.1002/1521-3773(20020301)41:5<834::AID-ANIE834>3.0.CO;2-V

An increasingly targeted functional motif in organic synthesis is the ubiquitous chiral β-amino alcohol. A novel two-step approach for the regio- and stereo-selective synthesis of a wide variety of 1,2-amino alcohols 4 involves the initial construction of chiral sulfamidates 3 from enantiopure diols 1, mediated by Burgess reagent (2, R = Me), followed by mild treatment with aqueous acid. Furthermore, the development of several new Burgess-type reagents 2 (R = CH₂Ph, CH₂-o-NO₂Ph, CH₂CHCH₂, CH₂CCl₃) greatly extends the applications of this protocol.

Full text of DOI:10.1002/1521-3773(20020301)41:5<834::AID-ANIE834>3.0.CO;2-V

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A Novel Regio- and Stereoselective Synthesis
of Sulfamidates from 1,2-Diols Using Burgess
and Related Reagents: A Facile Entry into
b-Amino Alcohols**
K. C. Nicolaou,* Xianhai Huang, Scott A. Snyder,
Paraselli Bheema Rao, Marco Bella, and Mali V. Reddy
Over the course of the past decade, chiral b-amino alcohols
have become an increasingly targeted functional motif in
organic synthesis owing to their ubiquity in biologically active
compounds, as well as their value as ligands in asymmetric
synthesis.[1, 2] Presently, several powerful methods exist to
enantioselectively create such synthons, foremost of which is
Sharpless' osmium-catalyzed asymmetric aminohydroxylation
(AA).[3] Although the utility of this reaction is unquestion-
able, variable regio- and enantioselectivity is still observed in
certain structural types, despite significant optimization of
reaction conditions.[4, 5] Herein we provide an alternative two-
step approach for the regio- and stereoselective synthesis of a
wide variety of 1,2-amino alcohols centered on initial
construction of chiral sulfamidates from enantiopure diols,
orchestrated by Burgess reagent (1, Scheme 1), followed by
mild treatment with aqueous acid. Furthermore, we disclose
the development of several novel Burgess-type reagents
which greatly extends the utility of this new protocol by
enabling access to an orthogonal set of N-protected sulfami-
dates.
Based on insight garnered during our program directed
towards the total synthesis of the marine-derived natural
product diazonamide A,[6] we reasoned that it might be
possible to generate a protected variant of a b-amino alcohol
in the form of a cyclic sulfamidate (III) by exposing a diol (I)
to excess Burgess reagent (1; Scheme 1).[7] Although this
chemical is typically employed as a powerful dehydrating
reagent (for example, effecting the formation of olefins from
alcohols),[8] we envisioned that after the generation of an
intermediate of type II from I, a unique and productive
cyclization to sulfamidate III through the proposed SN2
Scheme 1. Proposed conversion of diols I into cyclic sulfamidates III using
Burgess reagent (1), and proof of principle (2 !3). mom ˆ methoxymethyl.
mechanism could potentially occur in preference to typical
pathways that involve the loss of water. Assuming that this
transformation proceeds with displacement of the more
activated leaving group, then variation of the R1 and R2
substituents on enantiopure I would enable the stereo- and
regioselective synthesis of diverse sulfamidates.
Typically, sulfamidates are prepared from chiral b-amino
alcohol starting materials in several steps (based on the
number of protecting-group manipulations required), and are
then utilized to generate a diverse array of functionality based
on the established ability of this synthon to undergo highly
selective reactions with O-, S-, N-, C-, and F-based nucleo-
philes, to yield compounds of general structure IV.[9] As such,
the proposed synthesis of III would not only represent a more
efficient approach than is currently available, since the
nitrogen atom is concomitantly protected, but more signifi-
cantly because the technology does not rely on the use of b-
amino alcohol starting materials, it would provide a unique
way to prepare this important functional motif stereoselec-
tively from III simply by using water as a nucleophile. To test
this hypothesis, we heated a THF solution of diol 2 (synthe-
sized from the precursor olefin by dihydroxylation under
standard conditions) and 2.5 equivalents of Burgess reagent
(1)[10] at reflux for 1 h and, most gratifyingly, observed the
smooth formation of the desired sulfamidate 3 in 84% yield as
a single regioisomer (>98:2) based on NMR spectroscopic
analysis. Significantly, because attempted carbamate-based
AA[11] of 2 led to the desired product in modest yield with
little control of regioselectivity, while the Ritter reaction
under acidic conditions[12] led solely to decomposition, the
ease and selectivity of this particular Burgess-mediated
transformation was suggestive of a potentially highly useful
and applicable synthetic methodology.[13]
[*] Prof. Dr. K. C. Nicolaou, Dr. X. Huang, S. A. Snyder,
Dr. P. Bheema Rao, Dr. M. Bella, Dr. M. V. Reddy
Department of Chemistry and The Skaggs Institute
for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037(USA)
Fax : (‡1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, California 92093 (USA)
[**] We thank Professor K. Barry Sharpless for the gracious donation of
several of the starting diol substrates. We also thank Drs. D. H. Huang,
G. Suizdak, and R. Chadja for NMR spectroscopic, mass spectromet-
ric, and X-ray crystallographic assistance, respectively. Financial
support for this work was provided by The Skaggs Institute for
Chemical Biology, predoctoral fellowships from the National Science
Foundation and Pfizer (S.A.S.), a postdoctoral fellowship from The
Skaggs Institute for Chemical Biology (X.H.), and grants from
American Biosciences, Amgen, Array Biopharma, Boehringer-Ingel-
heim, Glaxo, Hoffman-LaRoche, DuPont, Merck, Novartis, Pfizer,
and Schering Plough.
834
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Angew. Chem. Int. Ed. 2002, 41, No. 5

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We then sought to test the generality of this reaction
process on a selection of styrene-derived diols that possessed
a broad range of aromatic substitution patterns in an effort to
explore the anticipated role of inductive effects on the
regioselectivity of the SN2-based cyclization. We examined
this particular class of compounds not only because it
represents the best substrates for Sharpless asymmetric
dihydroxylation (AD) in terms of both catalytic activity and
enantioselectivity,[14] but also because styrene-type olefins
display good but variable yields and regioselectivity in
carbamate-based AA.[11] As shown in Table 1, Burgess-
mediated sulfamidate synthesis followed the expected pattern
for inductive influence in nucleophilic displacement at the
benzylic position: electron-donating groups displayed excel-
lent regioselectivity (Table 1, entries 1 4), whereas a lower
selectivity was observed with electron-withdrawing substitu-
ents (Table 1, entries 6 and 7) relative to simple styrene
(Table 1, entry 5). In all cases, the products were formed in
high yield, and when two regioisomers were formed, the
majority were separable by chromatography. Significantly, the
poor regioselectivity observed in the conversion of 16 into 17
(Table 1, entry 7) was improved to 75:25 when the reaction
was carried out at ambient temperature, albeit at the expense
of yield (35%).
To explore the role of steric encumbrance on the reaction
process, and to test the applicability of the procedure for other
structural classes, we explored several additional substrates
(Table 2). As expected, increasing steric bulk at the terminal
position of the styrene core with a single methyl group
(Table 2, entries 1 and 2) dramatically increased the regiose-
lectivity of cyclic sulfamidate formation (cf. Table 1). Surpris-
ingly, substituents adjacent to the reactive benzylic center on
the aromatic ring did not affect either yield or selectivity
Table 1. Regioselective synthesis of sulfamidates from diols by using
Burgess reagent (1).
Table 2. Further examples of the regioselective synthesis of sulfamidates
from diols by using Burgess reagent (1).
Entry Starting material
Major product
Ratio of
Yield
regioisomers[a][%]
1
> 98:2
72
87
Entry Starting material
Major product
Ratio of
Yield
regioisomers[a] [%]
1
> 98:2
91
88
2
3
95:5
2
3
95:5
> 98:2
92
95:5
95:5
87
79
4
5
> 98:2
94
82
4
5
6
7
85:15
93:792
6
> 98:2
81
85:15
55:45
83
86
7
8
71:29
41
76
> 98:2
1
[a] Determined by means of H NMR spectroscopic analysis of the crude
reaction products.
[a] Determined by means of 1H NMR spectroscopic analysis of the crude
reaction products.
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(Table 2, entries 3 and 4). Additionally, esters were well-
tolerated in the reaction, with near complete regioselectivity
observed for the formation of 29 from 28 (Table 2, entry 6), as
a result of the mutually reinforcing effects of a-position
deactivation by the ester moiety and the steric bulk imposed
at that site by a methyl group. Competitive steric and
electronic effects (Table 2, entry 7) led to retarded SN2
displacement at the preferred terminal site, thereby reducing
both regioselectivity and yield. Finally, reactions with simple
aliphatic examples were highly regioselective, presumably
because of the well-established preference for nucleophilic
displacement of primary over secondary leaving groups. To
verify the potential of this reaction for asymmetric synthesis,
since all of the examples listed in Tables 1 and 2 were
performed on racemic diol substrates, an X-ray crystal
structure was obtained for sulfamidate 29 which confirmed
that inversion of stereochemistry had occurred at the benzylic
position relative to the racemic cis-diol starting material
(Figure 1).[15] Additionally, both racemic and enantiopure 26
were synthesized,[16] and comparison of the chiral HPLC
traces of the resultant products 27 indicated that preexisting
stereochemical information was communicated in the reac-
tion with complete fidelity.[17]
Scheme 2. Synthesis of the novel variants 39 42 of the original Burgess
reagent: a) chlorosulfonyl isocyanate (34, 1.0 equiv), ROH (1.05 equiv),
CH2Cl2, 08C, 30 min, 89 95%; b) Et3N (2.5 equiv), C6H6, 258C, 1 h, 81
87%.
Table 3. Use of the new Burgess-type reagents 39 42 to prepare orthogonally
protected sulfamidates 43 49.
Entry Starting material
Major product
Ratio of
Yield
regioisomers[a] [%]
1
> 98:2
90
81
2
3
95:5
> 98:2
87
4
5
> 98:2
> 98:2
82
89
Figure 1. X-ray crystal structure of sulfamidate 29.
To extend the overall utility of the present sulfamidate
synthesis, we next sought to create compounds bearing N
protection other than a methyl carbamate, a goal which could
be achieved simply through modification of 1. To our surprise,
however, such reagents represented novel chemical entities,
as an extensive search of the literature indicated that no
efforts had been expended to create any Burgess-type salts
other than those originally described almost thirty years ago.
This result was unexpected, as 1 is known to passess both
thermal and moisture sensitivity,[8a] features which might be
modulated by differentiation of the carbamate portion. We
readily prepared four different Burgess-type reagents (39
42), representing an orthogonal set of amine protecting
groups (based on deprotection by hydrogenation, photolysis,
exposure to palladium-based catalysts, or treatment with Zn,
respectively) simply by treating chlorosulfonylisocyanate (34)
with the alcohol of interest, followed by subsequent exposure
to Et3N (Scheme 2). The relative ease of these preparations
implies that virtually any carbamate-based Burgess-type salt
can be accessed by this approach.[18] Exposure of several diol
substrates to 39 42 resulted in the facile formation of the
desired sulfamidate products 43 49 (Table 3) in comparable
efficiency and selectivity as was observed previously with 1.
6
7
> 98:2
> 98:2
87
78
[a] Determined by means of 1H NMR spectroscopic analysis of the crude
ˆ
reaction products. Cbz ˆ CO2CH2Ph, Alloc ˆ CO2CH2CH CH2, Troc ˆ
CO2CH2CCl3.
Significantly, preliminary handling of 39 42 suggests that
they possess unique thermal and moisture-sensitivity profiles
relative to 1, physical features which could prove significant in
transformations that are typically effected by Burgess reagent
on recalcitrant substrates. The ability of 39 42 to perform
reactions already known with 1, such as oxazole formation
from precursor ketoamides,[19] is being explored.
836
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Finally, we sought to convert the sulfamidate products into
b-amino alcohols. Although this conversion had been dis-
closed previously in the literature (1:1 mixture of HCl (aq.)/
dioxane, ambient temperature), only one substrate was
examined.[9k] To verify that this deprotection protocol had
sufficient scope for general synthetic utility, several sulfami-
dates were readily deprotected under these conditions
(Table 4). High yields were observed in all examples, despite
relatively large variations in the reaction time necessary for
complete conversion.[20]
disclosed sulfamidate synthesis, as well as a full exploration
into the physical properties and chemical reactivity of the
newly disclosed Burgess-type reagents 39 42, are the subject
of present investigations.
Experimental Section
General procedure: the diol (0.5 mmol, 1.0 equiv) was dissolved in
anhydrous THF (5 mL) and 1 (0.293 g, 1.25 mmol, 2.5 equiv) was added.
The resultant solution was heated at reflux for 1 h, cooled to ambient
temperature, concentrated, and then purified by chromatography on silica
gel to afford the desired product in high purity.
Note: although analysis by thin-layer chromatography (TLC) indicates
complete consumption of starting materials after a few minutes, uncyclized
material II (Scheme 1) remains at the baseline, and further heating is
required to effect complete conversion into III.
Table 4. Deprotection of cyclic sulfamidates using aqueous HCl in dioxane at
ambient temperature to yield b-amino alcohols.
Entry Starting Material
Product
t [h] Yield [%]
Deprotection of the sulfamidate group: the substrate was dissolved in a
mixture of HCl (4m, aq.)/dioxane (1:1) and the solution was stirred at
ambient temperature until complete conversion was observed by TLC. The
reaction mixture was then diluted with EtOAc, washed with aqueous
NaHCO3 (5%) and brine, dried over MgSO4, and concentrated to afford
spectroscopically pure IV.
1
10
30
94
95
Received: November 23, 2001 [Z18267]
2
[1] For selected reviews on the synthesis and applications of 1,2-amino
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4
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39, 3667- 3670; d) M. Bruncko, G. Schlingloff, K. B. Sharpless, Angew.
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1483 1486.
7
16
90
[5] For an alternate and useful preparation of chiral 1,2-amino alcohols
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1995, 34, 1219 1222.
To summarize, a novel regio- and stereoselective two-stage
synthesis of b-amino alcohols has been achieved in which the
key transformation is the creation of a cyclic sulfamidate from
a precursor diol, mediated by Burgess-type reagents. The
generality and scope of this approach is underscored by the
considerable number and variety of substrates which display
high levels of selectivity in the process. As such, this method
provides facile access to compounds for use in a myriad of
applications, whether as chiral ligands to perform asymmetric
synthesis or as molecular probes to explore problems in
chemical biology. Further extensions of the utility of the
[6] For progress towards the total synthesis diazonamide A, see: a) K. C.
Nicolaou, S. A. Snyder, K. B. Simonsen, A. E. Koumbis, Angew.
Chem. 2000, 112, 3615 1620; Angew. Chem. Int. Ed. 2000, 39, 3473
3478; b) K. C. Nicolaou, X. Huang, N. Giuseppone, P. Bheema Rao,
M. Bella, M. V. Reddy, S. A. Snyder, Angew. Chem. 2001, 113, 4841
4845; Angew. Chem. Int. Ed. 2001, 40, 4705 4709; for the develop-
ment of other synthetic methodology as the result of this research
program in total synthesis, see: c) K. C. Nicolaou, S. A. Snyder, A.
Bigot, J. A. Pfefferkorn, Angew. Chem. 2000, 112, 1135 1138; Angew.
Chem. Int. Ed. 2000, 39, 1093 1096; d) K. C. Nicolaou, A. E.
Koumbis, S. A. Snyder, K. B. Simonsen, Angew. Chem. 2000, 112,
2629 2633; Angew. Chem. Int. Ed. 2000, 39, 2529 2533.
Angew. Chem. Int. Ed. 2002, 41, No. 5
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[7] a) G. M. Atkins, E. M. Burgess, J. Am. Chem. Soc. 1968, 90, 4744
4745; b) G. M. Atkins, E. M. Burgess, J. Am. Chem. Soc. 1972, 94,
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[8] For reviews on the chemistry of 1, see: a) P. Taibe, S. Mobashery in
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A Supramolecular Array of Fullerenes by
Quadruple Hydrogen Bonding**
¬
Luis Sanchez, Minze T. Rispens, and
Jan C. Hummelen*
Fullerenes have interesting properties that may be utilized
in a variety of applications including organic photovoltaic
(PV) devices.[1] Especially organic bulk-heterojunction PV
cells consisting of a blend of a p-conjugated polymer and a
fullerene derivative[2] have received much attention recently.
A way to improve the efficiency of these so called ™plastic∫
solar cells is the optimization of the morphology of the
photoactive layer. A potential way to attain this goal is
through supramolecular assembly of the constituents. Hydro-
gen bonding is particularly useful in the construction of
supramolecular structures.[3] Relatively little work on C60-
based polymers[4] and supramolecular C60 derivatives has been
performed.[5] So far, only dimeric compounds have been
obtained by a supramolecular approach.[6] Monofunctional-
ized C60 derivatives bearing one or two hydrogen-bonding
moieties on the substituent can serve as building blocks for the
preparation of fullerene-containing dimers and arrays, by
using the strength, directionality, and specificity, characteristic
of hydrogen bonding.[3] Our group[7] and the group of MartÌn[8]
have recently reported on the synthesis of supramolecular C60
dimers bearing Meijer×s self-complementary 2-ureido-4-pyr-
imidinones which have a donor donor acceptor acceptor
(DDAA) hydrogen bonding motif. This motif gives rise to a
very high dimerization constant (Kd ꢀ 6 Â 107 mÀ1), as a result
of attractive secondary interactions.[9] The presence of two
ureidopyrimidinone groups in a molecule results in supra-
molecular polymers of exceptional properties.[10] After our
first exercise on a fullerene with one coupling unit,[7] we now
report the synthesis and spectroscopic characterization of the
first hydrogen-bonded supramolecular array, formed by a
(methano)fullerene with two coupling units.
[9] a) L. Wei, W. D. Lubell, Org. Lett. 2000, 2, 2595 2598; b) L. T.
Boulton, H. T. Stock, J. Raphy, D. C. Horwell, J. Chem. Soc. Perkin
Trans. 1 1999, 1421 1429; c) D. Ok, M. H. Fisher, M. J. Wyvratt, P. T.
Meinke, Tetrahedron Lett. 1999, 40, 3831 3834; d) B. M. Kim, S. M.
So, Tetrahedron Lett. 1998, 39, 5381 5384; e) B. Aguilera, A.
¬
Fernandez-Mayorales, C. Jaramillo, Tetrahedron 1997, 53, 5863
5876; f) M. E. Van Dort, Y.-W. Jung, P. S. Sherman, M. R. Kilbourn,
D. M. Wieland, J. Med. Chem. 1995, 38, 810 815; g) K. K. Andersen,
M. G. Kociolek, J. Org. Chem. 1995, 60, 2003 2007; h) M. Okuda, K.
Tomioka, Tetrahedron Lett. 1994, 35, 4585 4586; i) K. K. Andersen,
D. D. Bray, S. Chumpradit, M. E. Clark, G. J. Habgood, C. D.
Hubbard, K. M. Young, J. Org. Chem. 1991, 56, 6508 6516; j) G. J.
White, M. E. Garst, J. Org. Chem. 1991, 56, 3177 3178; k) J. E.
Baldwin, A. C. Spivey, C. J. Schofield, Tetrahedron: Asymmetry 1991,
1, 881 884; l) D. Alker, K. J. Doyle, L. M. Harwood, A. McGregor,
Tetrahedron: Asymmetry 1991, 1, 877 880; m) T. A. Lyle, C. A.
Magill, S. M. Pitzenberger, J. Am. Chem. Soc. 1987, 109, 7890 7891.
[10] Although 1 is available from several commercial sources at prices
ranging from US$36 45 per gram, the material is easily synthesized
during the course of an afternoon in multigram quantities at a price of
less than US$1 per gram by following the procedure described in
ref. [7c].
[11] a) K. L. Reddy, K. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 1207
1217; b) G. Li, H. H. Angert, K. B. Sharpless, Angew. Chem. 1996, 108,
2995 2999; Angew. Chem. Int. Ed. Engl. 1996, 35, 2813 2817.
[12] a) C. M. Bellucci, A. Bergamini, P. G. Cozzi, A. Papa, E. Tagliavini, A.
Umani-Ronchi, Tetrahedron: Asymmetry 1997, 8, 895 902; b) C. H.
Senanayake, L. M. DiMichele, J. Liu, L. E. Fredenburgh, K. M. Ryan,
F. E. Roberts, R. D. Larsen, T. R. Verhoeven, P. J. Reider, Tetrahedron
Lett. 1995, 36, 7615 7618; c) C. H. Senanayake, F. E. Roberts, L. M.
DiMichele, K. M. Ryan, J. Liu, L. E. Fredenburgh, B. S. Foster, A. W.
Douglas, R. D. Larsen, T. R. Verhoeven, P. J. Reider, Tetrahedron
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[13] For alternate, multistep approaches to cis-1,2-amino alcohols from
diols, see: a) M. K. Lakshman, B. Zajc, Tetrahedron Lett. 1996, 37,
2529 2532; b) A. K. Ghosh, S. P. Mckee, W. M. Sanders, Tetrahedron
Lett. 1991, 32, 711 714.
The synthesis of target monomer 8 (Scheme 1) started with
the conversion of diethyl-4-oxopimelate (1) into para-tosyl-
hydrazone 2. Heating the anion of 2 in the presence of C60 in
1,2-ortho-dichlorobenzene (ODCB) at 1008C[11] gave fulle-
roid 3a, together with methanofullerene 3b, higher adducts,
and C60, through the intermediate diazo compound and
diazoline adduct. The isomeric mixture 3a/3b was isolated
and photoisomerized quantitatively to the [6,6]-isomer 3b.
Hydrolysis of 3b yielded acid 4, which was fully characterized
despite its insolubility in all common solvents. Target meth-
anofullerene 8 was prepared using a one-pot procedure:
[14] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994,
94, 2483 2547.
[15] This analysis does not exclude the possibility of inversion at the other
center. However, this event is highly unlikely based on mechanistic
details elucidated thus far. CCDC-174599 (29) contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB21EZ, UK; fax: (‡44)1223-336-033; or deposit
@ccdc.cam.ac.uk).
[16] Enantiopure (R)-26 was prepared by using AD-mix-b: H. Becker,
S. B. King, M. Taniguchi, K. P. M. Vanhessche, K. B. Sharpless, J. Org.
Chem. 1995, 60, 3940 3941.
[17] Chiral HPLC analysis was performed by using a Diacel Chiralpack
Column AD, hexane/2-propanol (85:15), 1.5 mLminÀ1
, 254 nm,
¬
[*] Prof. Dr. J. C. Hummelen, Dr. L. Sanchez, Dr. M. T. Rispens
8.72 min ((S)-27), 12.2 min ((R)-27).
Stratingh Institute and Materials Science Centre
University of Groningen
[18] Although carbamate-derived Burgess-type salts should be quite
stable, the corresponding amide-based compounds are unlikely to be
readily isolated; for efforts to use such reagents in synthesis, see:
ref. [7c] and H. Vorbruggen, K. Krolikiewicz, Tetrahedron 1994, 50,
6549 6558.
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Fax : (‡31)50-3634296
E-mail: J.C.Hummelen@chem.rug.nl
[**] These investigations were financially supported by the Dutch Minis-
tries of EZ, O&W, and VROM through the EET program
(EETK97115). We thank Prof. Bert Meijer and his co-workers for
sharing their know-how and open discussions.
[19] For representative examples, see: ref. [6b] and C. T. Brain, J. M. Paul,
Synlett 1999, 1642 1644.
[20] The chiral integrity of products that result from ring opening of the
chiral sulfamidate by water under acidic conditions followed by
neutralization with aqueous sodium bicarbonate has already been
verified on a substrate far more prone to racemization (see: ref. [9k]).
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
838
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4105-0838 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 5